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Recent Developments in the Medicinal Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes
J.W. Huffman* and L.W. Padgett
H. L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina 29634-0973, USA
Abstract: During the development of new nonsteroidal anti-inflammatory agents, it was discovered that 1aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB1 ) receptor. This has led to the development of over 100 cannabimimetic aminoalkylindoles, and the development of SAR for these compounds. Later work demonstrated that the aminoalkyl moiety was not necessary, and could be replaced by a four- to sixmembered alkyl chain without loss of affinity. Investigation of these indoles led to the discovery of a CB2 selective ligand, 3-(1-naphthoyl)-N-propylindole. Subsequent work has provided several additional CB2 selective indoles. On the basis of a proposed pharmacophore for the cannabimimetic indoles, a series of pyrroles and indenes were developed, some of which are potent cannabinoids. SAR for several series of pyrroles have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB1 receptor. There is some evidence that the indoles bind to a somewhat different site on the receptor than traditional cannabinoids, and interact with the receptor primarily by aromatic stacking.

Keywords: Cannabinoid, aminoalkylindole, pyrrole, indene, receptor, indole. INTRODUCTION In the years following the elucidation of the structure of 9-tetrahydrocannabinol ( 9-THC, 1), the principal psychoactive constituent of marijuana (Cannabis sativa L.) [1], a comprehensive set of structure-activity relationships (SAR) based on the partially reduced dibenzopyran structure of THC was developed [2-5]. Subsequently, a group at Pfizer developed a series of very potent non-traditional cannabinoids [6-9]. These SAR were extended to the Pfizer compounds, which lack the dibenzopyran ring present in traditional cannabinoids, but exhibit typical cannabinoid pharmacology. CP-55,940 (2, DMH = 1,1-dimethylheptyl) is representative of this group of compounds, and is almost certainly the most well-known of these Pfizer non-traditional cannabinoids.
CH3 OH OH H3C H3C O 1 CH3
2

subsequent work from the same group confirmed that compounds of this group bind to the cannabinoid brain receptor, some with quite high affinity [11]. One rigid AAI, WIN-55,212-2 (4), has particularly high affinity for the cannabinoid receptors, and has been employed extensively in a number of investigations into the pharmacology of this group of compounds.
O O

H3C H3CO H3C N N N O O 3 4

N O

OH

Fig. (2). Structures of pravadoline and WIN-55,212-2.

DMH

HO

Fig. (1). Structures of 9 -THC and CP 55,940.

In 1991, a group at Sterling Winthrop reported that pravadoline (3) and related compounds inhibited the contractions of the electrically stimulated mouse vas deferens (MVD), are antinociceptive in vivo and inhibit adenylate cyclase [10]. These aminoalkylindoles (AAIs) were found to interact with a G-protein coupled receptor in the brain, and
*Address correspondence to this author at the H. L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina 29634-0973, USA; E-mail: huffman@clemson.edu 0929-8673/05 $50.00+.00

A few years later, Huffman et al. found that the aminoalkyl portion of the molecule could be replaced by an alkyl group to provide indole derivatives, such as JWH-007 (5), that exhibit typical cannabinoid pharmacology [12]. It was also found that the benzene ring of the indole is not essential for either receptor affinity or in vivo effects, and cannabimimetic pyrrole derivatives (6, R = various alkyl groups) were reported by the Clemson group [13]. A detailed presentation of the SAR, of several of these cannabimimetic indoles and pyrroles was published several years ago [14]. Several aminoalkylindenes structurally related to the cannabimimetic AAIs have also been prepared, some of which have high affinity for the cannabinoid receptors [15, 16]. In these compounds, the indole nitrogen is replaced with a carbon atom to give 7 and similar compounds.
2005 Bentham Science Publishers Ltd.

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N H3C N R 5 R = n- C5H11, R' = H 8 R = n-C3H7, R' = H 9 R = n-C3H7, R' = CH3 O 6 7 R N

Fig. (3). Structures of cannabimimetic indoles, pyrroles and indenes.

The chemistry and pharmacology of cannabimimetic indoles, including the aminoalkylindoles, and the related pyrroles and indenes were reviewed in 1999 [17]. The present review will cover developments in this field from late 1998 through mid-2004. The similarities and differences in the interactions of these compounds and traditional cannabinoids with cannabinoid receptors will be discussed. Prior to describing the medicinal chemistry and pharmacology of these compounds, a brief introduction to some of the more common methods employed to evaluate the pharmacology of cannabinoids will be described. PHARMACOLOGY METHODS A cannabinoid receptor in rat brain was first described in 1988 [18]. This G-protein coupled receptor was subsequently cloned, and the primary structure was determined [19]. A human cannabinoid central nervous system receptor has been identified, which is virtually identical (97% homology) to that from the rat [20]. It is generally accepted that the overt physiological effects of cannabinoids are mediated through this receptor [21, 22]. In 1993, a second human cannabinoid receptor which shows 44% identity to the brain receptor was identified and cloned [23]. The transmembrane portion of this receptor shows 66% identity to the central nervous system receptor. This receptor is found primarily in the immune system [24]. The central nervous system receptor is designated as the CB1 receptor, and that found principally in the immune system as the CB2 receptor. Affinity for the CB1 receptor measures the ability of the substrate to displace a potent cannabinoid, usually tritiated CP-55,940 (2), from its binding site in a membrane preparation as described by Compton et al. [22]. Alternatively, the displacement of tritiated WIN-55,212-2 (4) has been employed [11]. Affinity for the CB2 receptor is determined by the ability of a ligand to displace CP-55,940 (2) from its binding site in transfected cell lines [23, 25, 26] or a mouse spleen membrane preparation [27]. An alternative method for the in vitro evaluation of cannabinoid activity employs the inhibition of electrically evoked contractions of the isolated mouse vas deferens (MVD) [28]. Two functional assays are employed to determine the efficacy of cannabinoid receptor ligands at both CB1 and CB 2. One of these measures the agonist induced attenuation of the ability of forskolin to stimulate the production of cAMP [28]. The other assay measures the ability of a cannabinoid receptor ligand to stimulate GTP S binding

[29]. This functional assay measures G-protein coupled receptor activation using [35S]GTP S binding. The most common in vivo protocol is a mouse model [21], in which a battery of three or four procedures is employed. These measure spontaneous activity (SA), antinociception (as tail flick, TF), hypothermia (as decrease in rectal temperature, RT) and catalepsy (as ring immobility, RI). A variety of other procedures have been employed to evaluate in vivo pharmacology, however the mouse model is widely accepted, and this protocol was used for the majority of the compounds discussed in this review that were evaluated in vivo. An extensive review of cannabinoid receptors and the pertinent bioassays has been published recently [30]. CANNABIMIMETIC INDOLES Following the observation that pravadoline (3) inhibited contractions of the electrically stimulated MVD [10], the group at Sterling Winthrop carried out an extensive study of the SAR of well over 100 related compounds [11, 31]. Subsequently, a series of sterically constrained AAIs was prepared, and it was found that the most effective compound in MVD activity was WIN-55,212-2 (4). These analogs were also evaluated in a binding assay, in which the ability of the ligand to displace tritiated 4 from its binding site in a rat brain membrane preparation was measured. There was a positive correlation between these binding data and the MVD assay, and it was concluded that there were many similarities both in vitro and in vivo, between the AAIs and traditional cannabinoids. Confirmatory evidence that the AAIs and traditional cannabinoids bind to the same receptor was found by Kuster et al. who determined the affinities of several AAIs for the WIN-55,212-2 binding site [32]. These compounds were also evaluated in the standard behavioral protocol for cannabinoids, and were found to exhibit typical cannabinoid pharmacology [33]. The Winthrop group reported well over 100 various cannabimimetic indoles, all of which belong to the subgroup of aminoalkylindoles [10, 11, 31, 34]. These workers stated that the necessary criteria for CB1 receptor affinity includes an aroyl group at C-3 of the indole, which, for maximum affinity should be 1-naphthoyl or substituted 1naphthoyl. However, no SAR for aromatic substituents were presented [31]. Other polycyclic aromatics at C-3 were less effective than naphthalene. A number of substituted 3benzoylindoles were described, however, they had uniformly

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R'

R'

N R 11 R = H 14 R' = CH3

CH3O

R'

R 10 R' = H 13 R' = CH3

R 12 R = H 15 R' = CH3

Fig. (4). Structures of various cannabimimetic indoles. R = C3 H 7 or C5 H 11 .

low affinity for the receptor. At C-2 of the indole, a group larger than methyl destroyed activity, and a hydrogen at C-2 was slightly superior to a methyl group. This group stated that an aminoethyl group appended to the indole nitrogen was optimum for cannabinoid activity, and that a cyclic amine, such as morpholine, piperidine or thiomporpholine was necessary as part of the aminoethyl group. Subsequent to outlining these SAR, the Winthrop group employed CoMFA to develop a pharmacophore for the aminoalkyl subgroup of the cannabimimetic indoles [35]. These authors concluded that it was probable that these indole analogues and classical cannabinoids may partly overlap in their interactions with the CB1 receptor, however no specific areas of commonality were suggested. In 1996, Showalter et al. reported that JWH-015, 1propyl-2-methyl-3-(1-naphthoyl)indole (8) has selective affinity for the CB2 receptor [25]. This observation, plus efforts to establish SAR for the cannabimimetic indoles led Huffman et al. to prepare a number of indole derivatives, some of which are very potent cannabinoids [12, 14, 36]. The principal difference between the SAR described by this group and that of the Winthrop workers is the finding that
Table 1.

the aminoalkyl group is not necessary for cannabimimetic activity, but that an alkyl substituent of four to six carbon atoms on nitrogen is necessary [12, 14, 36]. CB1 receptor affinity and in vivo potency are maximized with an N -pentyl substituent. For useful CB2 receptor selectivity, high affinity for this receptor with minimum affinity for the CB1 receptor is essential. Both JWH-015 and another CB2 selective indole, JWH-046, 1-propyl-2-methyl-3-(7-methyl-1naphthoyl)indole (9), have a propyl substituent on nitrogen, and in the effort to develop CB2 selective compounds, emphasis was placed on preparing N -propyl indoles. For developing SAR at the CB1 receptor N -pentyl substituents were employed. In agreement with the Winthrop data, a 2methyl group slightly attenuates activity relative to an unsubstituted 2-position, and larger substituents lead to inactivity [36]. Various 3-(1-naphthoyl) substituents were investigated and it was found that a 7-methyl substituent has little effect on activity, while a 4-methoxy group enhances affinity for the CB1 receptor [36]. Larger 4-alkoxyl groups effectively render the compound inactive. Receptor affinities and in vivo potencies of several N -propyl- and N -pentyl-3-(1naphthoyl)indoles (10), 3-(7-methyl-1-naphthoyl)indoles

Receptor Affinities (CB 1 and CB 2 ) and In Vivo Potency for Cannabimimetic Indoles 1015, WIN-55,212-2 (4) and 9 -THC (1)
Compound Ki (nM) (CB1 ) 412b 1.90.1 b 38372b 105055c 9.54.5b 9.54.5d 21411f 34338e 111e 633e 47667e 1.20.1e 4.50.1e Ki (nM) (CB2 ) 3610 b 0.30.2b 145b 17054e 2.92.6b 2.92.6e 10646f 165e 0.50.1e 326e 973e 122e 1.90.3e ED50 SA 0.92 0.25c 18.7 NT 0.44 0.70 NT No Max <2.7 e 5.5f NT 0.15f NT mol/kga TF 2.7 0.82c 84.7 NT ~0.09 0.25 NT No Max <2.7 e 10f NT 0.22f NT RT

9 - THC (1)

2.5 23.0c 99.1 NT 1.7 4.3 NT No Max <2.7 e 12.3f NT 0.17f NT

WIN-55212-2 (4) 8 (JWH-015) 10, R = n-Propyl (JWH-072) 10, R = n-Pentyl (JWH-018) 13, R = n-Pentyl (JWH-007) 11, R = n-Propyl (JWH-076) 14, R = n-Propyl (JWH-046) 14, R = n-Pentyl (JWH-048) 12, R = n-Propyl (JWH-079) 15, R = n-Propyl (JWH-094) 12, R = n-Pentyl (JWH-081) 15, R = n-Pentyl (JWH-098)

a Refs. 12, 14 and 36. b Ref. 25. c Ref. 33. d Ref. 14. e Ref. 37. f Huffman et al. unpublished work.

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H3CO

R'

N R

C2H5

N R

16 R = C3H7, R' = C 4H9 17 R = C4H9, R' = C 5H11 18 R = C5H11, R' = C6H13

19 R = C3 H7 to C7H15

Fig. (5). Structures of 2-alkyl cannabimimetic indoles.

(11), 3-(4-methoxy-1-naphthoyl)indoles (12) and the corresponding 2-methylindoles (13, 14, 15) are presented in Table 1. Data for ( 9-THC, 1) and WIN-55,212-2 are also included in Table 1. The CB 1 and CB2 receptor affinities for 34 cannabimimetic indoles 1015 were reported by Aung et al. in 2000 [37]. The receptor affinities and some in vivo pharmacology for these compounds had been presented previously [17, 36, 38], and the data for those compounds in which R = C3H7 and R = C5H11 are included in Table 1. The N -alkyl substituents were varied from methyl through nheptyl, and in accordance with earlier work, it was found that a nitrogen substituent of four to six carbon atoms provided maximum affinity for the CB1 receptor [12, 14. 17]. In general, indoles with an n-propyl group appended to nitrogen have little affinity for the CB1 receptor, but JWH079, 1-propyl-3-(4-methoxy-1-naphthoyl)indole (12, R = C 3H7, Table 1) is an exception. This compound has moderate affinity for the CB 1 receptor with Ki = 63.0 3.0 nM. None of the indole derivatives with N-methyl or N ethyl groups have appreciable affinity for the CB1 receptor [37]. The1-alkyl-2-methyl-3-(4-methoxy-1-naphthoyl) indoles (15, R = C3H7, JWH-094, R = C4H9, JWH-096 and R = C 5H11, JWH-098) were prepared by base catalyzed alkylation of 2-methyl-3-(4-methoxy-1-naphthoyl) indole (15, R = H). As a side reaction, alkylation of the 2-methyl group occurred to give indoles 16-18. Unexpectedly, 1propyl-2-butylindole, JWH-093 (16) had rather high affinity for the CB1 receptor with Ki = 40.7 2.8 nM [37]. Neither the 1-butyl-2-pentyl- (17, JWH-095) nor the 1-pentyl-2hexylindole (18, JWH-097) had significant affinity for the CB 1 receptor. A series of 2-ethylindoles (19, R = C3H7 through R = C7H15) was prepared [38]. In this series only JWH-116, the n-pentyl compound (19, R = C5H11), has significant affinity for the CB1 receptor with Ki = 52 4.9

nM. None of the other compounds in this series have Ki < 200 nM. With the exception of indole 16, the weak affinities of these 2-alkylindoles is in accord with the generalization that an alkyl group larger than methyl at the indole C-2 position leads to a loss of affinity for the CB1 receptor [10, 11]. The CB2 receptor affinities for cannabimimetic indoles 10-15 follow the same general trend as their CB1 receptor affinities [37]. Those compounds with N -methyl or N -ethyl substituents have little affinity for the CB2 receptor, and the CB 2 affinities tend to increase with increasing alkyl chain length up to n-hexyl, then decrease by several orders of magnitude with the n-heptyl nitrogen substituent. However, within any series of indoles 10-15, there is much less variation in the CB2 receptor affinities for those compounds with n-propyl to n-hexyl nitrogen substituents. For instance, in compounds 15, the CB1 receptor affinities range from 476 67 nM for JWH-094 (15, R = (C 3H7) to 4.5 0.1 nM for JWH-098 (15, R = C 5H11). In contrast, the CB2 affinitiesfor the same series vary from 1.9 0.3 nM for the pentyl analog, JWH-098, to 97 2.7 nM for the propyl compound, JWH-094. While many of these compounds have some selectivity for the CB2 receptor, only two, JWH-015 (8) and JWH-046 (9) have the combination of low affinity for the CB 1 receptor and high affinity for the CB2 receptor that is necessary for a useful CB2 selective ligand [37]. The rationale for replacing the N -aminoalkyl substituent characteristic of the Winthrop cannabimimetic indoles with an N -alkyl group was based upon molecular modeling studies in which it was suggested that the naphthoyl carbonyl would correspond to the phenolic hydroxyl of traditional cannabinoids [12, 14]. The 7- and 8-positions of the naphthalene were overlaid upon C-9 and C-10 of THC, in which alignment the indole nitrogen corresponds to the first carbon atom of the cannabinoid side chain (C-1'). For the purpose of modeling, the side chain of THC was
a

CH3 a b c OH d e H3C H3C O 32 f CH3

b c O d e H3 C N

f O

N(CH3) 2 33

Fig. (6). Suggested alignment of traditional cannabinoids and AAIs [Refs. 12, 14].

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truncated by one carbon atom, and the morpholine was modeled as a dimethylamino group (Fig. 6). The conclusion was reached that if this alignment was correct, the aminoalkyl group was not essential for cannabinoid activity and could be replaced by other substituents. This alignment was used to design the cannabimimetic indoles prepared by the Clemson group [12, 14, 36, 37]. However, experiments using mutant CB1 receptors led to the suggestion that cannabimimetic indoles and traditional cannabinoids, such as 9-THC (1) bind to different, but partially overlapping sites on the receptor [39, 40]. These experiments, combined with molecular modeling studies, led to a hypothesis that a hydrogen bonding interaction of a lysine on the third transmembrane domain of the CB1 receptor is important in the binding of traditional cannabinoids such as 9-THC (1), but not cannabimimetic indoles [16, 41]. In order to test the hypothetical alignment of traditional cannabinoids and cannabimimetic indoles that was employed in the design of the indoles synthesized by the Huffman group, a hybrid cannabinoid (20, JWH-161) that combined structural features of both traditional cannabinoids and cannabimimetic indoles was synthesized [42]. This hybrid cannabinoid has high affinity for the CB1 receptor, with Ki = 19 3 nM. The compound is potent in vivo with ED 50 = 2.7, 6.2 and 3.0 mole/kg for spontaneous activity (SA), tail flick (TF) and rectal temperature (RT), respectively. It is slightly less potent than 9-THC (1 Table 1) in spontaneous activity and tail flick, but approximately equivalent to THC in the rectal temperature measure of hypothermia.
CH3 OH

supports both the alignment suggested in Figure 6 and the hydrogen bonding hypothesis. However, there is a body of evidence suggesting that the cannabimimetic indoles probably interact with the CB1 receptor primarily by aromatic stacking interactions [16, 43]. To test the hypothesis that hydrogen bonding interactions involving the indole carbonyl group are not important in the interaction of cannabimimetic indoles with the CB 1 receptor, a series of 3-indolyl-1-naphthylmethanes (21-26) was prepared and their affinities for the CB1 receptor were determined [44]. The CB1 receptor affinities of these compounds and the corresponding naphthoylindoles are summarized in Table 2. The CB1 receptor affinities of indoles 2123 (JWH-175, JWH-184 and JWH-185), which are unsubstituted at the C-2 position of the indole, are essentially identical with Ki = 17 23 nM. These affinities are somewhat less than those of the corresponding naphthoylindoles, JWH-018 (10, R = C 5H11), JWH-122 (27) and JWH-081 (12, R = C5H11), which have Ki = 9 5, 0.69 0.05 and 1.2 0.1 nM, respectively. Although the presence of a methyl or methoxy group at the 4-position of the naphthoyl group causes a significant increase in affinity for JWH-122 and JWH-127, in the case of indolylnaphthylmethanes 2123, there is little effect on CB1 receptor affinity associated with substitution at C-4. In contrast to the naphthoylindole series in which a methyl group at C-2 of the indole causes only slight attenuation of CB1 receptor affinity, indolylnaphthylmethanes 2426 (JWH-196, JWH-194 and JWH-197, respectively) have considerably reduced affinity with Ki = 151323 nM. A structural characteristic of the Winthrop cannabimimetic indoles is the presence of an aminoalkyl group appended to the indole nitrogen [10, 31]. This aminoalkyl group could conceivably interact with the CB1 receptor by hydrogen bonding as suggested by Xie et al. [45]. To explore this possibility, aminoalkylindoles 29 (JWH-195), 30 (JWH-192) and 31 (JWH-199), which lack the carbonyl oxygen, and the corresponding naphthoyl analogs, JWH-200 (32), JWH-193 (33) and JWH-198 (34), were prepared and their affinities for the CB1 receptor were determined. The CB1 receptor affinities for aminoalkylindoles 2934 are included in Table 2. Although there is little variation in CB1 receptoraffinity as a function of substitution at C-4 of the naphthalene moiety in indoles 2123, there is considerable variation in the affinities of aminoalkylindoles 2931. The unsubstituted analog, JWH-195 (29), has modest affinity for the CB1
O

H3C H3C O 20 N C5H11

Fig. (7). Structure of JWH-161.

The alignment of 9-THC and cannabimimetic indoles depicted in Fig. (6) includes the hypothesis that the indole carbonyl interacts with the CB1 receptor by hydrogen bonding and was supported by the receptor affinities and in vivo potencies of the cannabimimetic indoles, both those with aminoalkyl groups and those with alkyl side chains. Also, the high affinity and in vivo potency of JWH-161 (20)

R'

H3C

N C5H11

C5H11 21 R, R' = H 22 R = CH3, R' = H 23 R = OCH3, R' = H 24 R = H, R' = CH3 25 R = CH3, R' = CH3 26 R = OCH3, R' = CH3

27 R = H 28 R = CH3

Fig. (8). Structures of indolylnaphthylmethanes and 3-(4-methyl-1-naphthoyl)indoles.

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Table 2. CB 1 Receptor Affinities (mean SEM) of Cannabimimetic Indoles 10, 12, 15, and 2134 [44]
Compound 1-Pentyl-1H-indol-3-yl-(1-naphthyl)methane (21, JWH-175) 1-Pentyl-1H-indol-3-yl-(4-methyl-1-naphthyl)methane (22, JWH-184) 1-Pentyl-1H-indol-3-yl-(4-methoxy-1-naphthyl)methane (23, JWH-185) 2-Methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methane (24, JWH-196) 2-Methyl-1-pentyl-1H-indol-3-yl-(4-methyl-1-naphthyl)methane (25, JWH-194) 2-Methyl-1-pentyl-1H-indol-3-yl-(4-methoxy-1-naphthyl)methane (26, JWH-197) 1-Pentyl-3-(1-naphthoyl)indole (10, R = C5 H11 , JWH-018) 1-Pentyl-3-(4-methyl-1-naphthoyl)indole (27, JWH-122) 1-Pentyl-3-(4-methoxy-1-naphthoyl)indole (12, R = C5 H11 , JWH-081) 2-Methyl-1-pentyl-3-(1-naphthoyl)indole (13, R = C5 H11 , JWH-007) 2-Methyl-1-pentyl-3-(4-methyl-1-naphthoyl)indole (28, JWH-149) 2-Methyl-1-pentyl-3-(4-methoxy-1-naphthoyl)indole (15, R = C5 H11 , JWH-098) 1-[2-(4-Morpholino)ethyl]-1H-indol-3-yl-1-naphthylmethane (29, JWH-195) 1-[2-(4-Morpholino)ethyl]-1H-indol-3-yl-(4-methyl-1-naphthyl)methane (30, JWH-192) 1-[2-(4-Morpholino)ethyl]-1H-indol-3-yl-(4-methoxy-1-naphthyl)methane (31, JWH-199) 1-[2-(4-Morpholino)ethyl]-3-(1-naphthoyl)indole (32, JWH-200) 1-[2-(4-Morpholino)ethyl]-3-(4-methyl-1-naphthoyl)indole (33, JWH-193) 1-[2-(4-Morpholino)ethyl]-3-(4-methoxy-1-naphthoyl)indole (34, JWH-198)
a Ref. 14. b Ref. 37.

Ki (nM) 22 2 23 6 17 3 151 18 127 19 323 28 9 5a 0.69 0.05 1.2 0.1b 9.5 4.5a 5.0 2.1 4.5 0.1b 113 28 41 13 20 2 42 5 61 10 2

receptor with Ki = 113 28 nM. The 4-methylnaphthyl compound, JWH-192 (30) has significantly greater affinity, Ki = 41 13 nM and the 4-methoxy analog has still greater affinity with Ki = 20 2 nM. Naphthoyl aminoalkylindoles 3234 had been reported previously by the Winthrop group who observed the same trend in relative CB1 receptor affinities, with the 4-methyl-1-naphthoyl- (33) and 4methoxy-1-naphthoylindoles (34) having greater affinity than the unsubstituted analog ( 32) [31].
X

interact with the receptor by hydrogen bonding. To explore this possibility, E-naphthylideneindene 35 (JWH-176) was prepared and was found to have high affinity for the CB 1 receptor with Ki = 26 4 nM [44].

C 5H11 R' 29 X = H2, R' = H 30 X = H2, R' = CH3 31 X = H2, R' = OCH3 32 X = O, R' = H 33 X = O, R' = CH3 34 X = O, R' = OCH3 N 35

Fig. (10). Structures of JWH-176.

N

Fig. (9). Structures of aminoalkylindoles.

E-Naphthylideneindene 7 has good affinity for the CB1 receptor with Ki = 2.72 0.22 nM, and modeling studies support the hypothesis that 7 and other cannabimimetic indenes interact with the receptor by aromatic stacking interactions [16]. However, there is at least a formal possibility that the morpholino nitrogen or oxygen may

The high CB1 receptor affinities of indoles 2123, 30, 31 and indene 35 strongly support the hypothesis that cannabimimetic indoles and related CB1 receptor ligands interact with the receptor primarily by aromatic stacking [16, 43]. In particular, the high affinity of indene 35, a hydrocarbon, for the CB1 receptor provides compelling evidence against hydrogen bonding interactions playing a major role in the binding of these ligands [44]. Indoles 2123, 30 and 31, which are unsubstituted at the C-2 position, have significant affinity for the CB1 receptor, however 2-methylindoles, 2426, have little affinity, in

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contrast to the 3-(1-naphthoyl)indole series in which the 2methylindoles have only slightly less affinity for the CB1 receptor than the unsubstituted compounds. There appeared to be no a priori explanation for the poor receptor affinities of indoles 2426, in comparison to the significant affinities of indoles 2123, 30 and 31. To obtain insight into the origin of these differences in receptor affinity, molecular modeling and receptor docking studies of indoles JWH-081 (12, R' = C5H11), its 2-methyl congener, JWH-098 (15, R' = C 5H11) and the corresponding pair of naphthylmethanes JWH-185 (23) and JWH-197 ( 26) were carried out [44]. 3-(1-Naphthoyl)indoles have been shown to exist in two principal conformations, either s-cis or s-trans. In the s-cis conformation, which predominates when the C-2 substituent is methyl, the carbonyl oxygen is near C-2 with the naphthalene ring stacked over C-4. In the s-trans conformation, which predominates when the C-2 substituent is hydrogen, the carbonyl oxygen is near C-4 of the indole, and the naphthalene ring is near C-2 [16]. Consistent with these earlier findings JWH-081 (12, R' = C5H11), with a hydrogen at C-2, has an s-trans conformation as the global minimum energy conformer. In JWH-098 (15, R' = C5H11), calculations revealed that the lowest energy conformer is an s-cis conformer. The lowest energy s-trans conformation of JWH-098 was found to be 1.22 kcal/mol higher in energy than the global minimum s-cis conformer [44]. 1-Pentyl-1H-indol-3-yl-(4-methoxy-1-naphthyl)methane (23, JWH-185, Ki = 17 3 nM) and 2-methyl-1-pentyl-1Hindol-3-yl-(4-methoxy-1-naphthyl)methane (26, JWH-197, Ki = 323 48 nM) are analogs of JWH-081 (12, R' = C 5H11) and JWH-098 (15, R' = C 5H11), respectively, in which the carbonyl bridge has been replaced by a methylene group. This replacement changes the hybridization of the bridging carbon from sp2 in the carbonyl group, to sp3 in the methylene group. This changes the relative orientation of the naphthalene and indole rings, compared to that in JWH-081, JWH-098 and WIN-55,212-2 (4). For JWH-185 and JWH197, the global minimum energy conformers have the methylene C-H bonds staggered, with respect to the indole ring. In this conformer, the naphthalene ring is oriented perpendicular to the plane of the indole nucleus. 1-Pentyl-1H-indol-3-yl-(4-methoxy-1-naphthyl)methane (23, JWH-185) has attenuated CB1 receptor affinity (Ki= 17 3 nM), relative to 1-pentyl-3-(4-methoxy-1naphthoyl)indole (12, R' = C5H11, JWH-081, Ki= 1.2 0.03 nM). Also in the 3-(1-naphthoyl)indole series (12, R' = C 5H11 and 15, R' = C5H11), the substitution of a methyl group at C-2 results in only a slight decrease in CB1 receptor affinity (JWH 081, 12, R' = C 5H11, K i = 1.2 0.03 nM; JWH 098, 15, R' = C 5H11, Ki = 4.5 0.1 nM). However, substitution at C-2 in the naphthylmethane series (23 and 26) results in a more profound 19-fold affinity loss (JWH 185, 23, K i = 17 3 nM; JWH 197, 26, Ki= 323 48 nM). In order to probe the origin of these affinity changes, each of these compounds was docked in a model of the active state (R*) of the CB 1 receptor. Cannabimimetic indoles are highly aromatic ligands, and CB 1 receptor mutation studies in which a lysine on transmembrane helix 3 is replaced with alanine indicate that this lysine is not an interaction site for WIN-55,212-2 (4) [39]. On this basis it was suggested that aromatic stacking

rather than hydrogen bonding interactions, are the primary interactions for cannabimimetic indoles at CB1 [41]. Cannabimimetic indoles 12, R' = C5H11 and 15, R' = C 5H11, 23 and 26 are structurally related to WIN-55,212-2 (4), and it was hypothesized that the TMH 3-4-5-6 region of CB 1 receptor would also be the binding region for these ligands. Indoles 12, R' = C5H11 and 15, R' = C 5H11 were docked in this region of the receptor in their lowest energy strans conformations, and indoles 23 and 26 were docked in this same region using the global minimum energy conformer of each. A hydrophobic binding pocket comprised of a valine, an isoleucine and a phenylalanine on helix-3, plus leucine and an isoleucine on helix-6 were identified, which permitted simultaneous interaction of the indole and naphthalene rings with the aromatic residues in the TMH 3-4-5-6 region of the CB 1 receptor active state (R*). When the alkyl chain on nitrogen was docked in this pocket, JWH-081 (12, R' = C 5H11) and JWH-098 (15, R' = C5H11) found aromatic stacking interactions with two tryptophan residues on helix5 of the CB1 receptor. In this docking position, the C-2 methyl group of JWH-098 would cause no loss of affinity, since the C-2 methyl group occupies an open space in the receptor binding pocket. The global minimum energy conformers of JWH-185 (23) and JWH-197 (26) were docked in the same general region of the CB1 receptor. However, because these analogs have conformations which orient the naphthalene and indole rings in a very different arrangement than in 3-aroylindoles, the orientation of the ligands in the binding pocket differs from that of JWH-081 and JWH-098. Naphthylindoles 23 and 26, retain the stacking interactions with the tryptophan residues on helix-5, and have an additional stacking interaction with a phenylalanine on helix-3, which involves the hydrogen at C-2 of the indole. While the 2-methyl analog JWH-197 (26), can engage in aromatic stacking interactions with the tryptophan residues on helix-5 of the CB 1 receptor, no aromatic stacking interaction is possible with phenylalanine on helix-3, because indole 27 lacks the hydrogen at C-2. The nearly 20-fold drop in affinity between JWH-185 and JWH-197 is consistent with the loss of an aromatic stacking interaction [41]. The significant affinities of indoles 21-23, 30, 31 and indene 35, none of which can interact with the CB1 receptor by hydrogen bonding, strongly support the hypothesis that cannabimimetic indoles interact with the receptor primarily by aromatic stacking interactions. The molecular modeling and receptor docking studies agree with this conclusion, and provide an explanation for the observation that 2methylindole analogues JWH-196 (24), JWH-194 (25) and JWH-197 (26) have greatly attenuated affinities for the CB 1 receptor. The Huffman group has very recently described the synthesis, CB 1 and CB2 receptor affinities for 47 indole derivatives [46]. Their goal was the development of structure-activity relationships for cannabimimetic indoles at both receptors, and if possible, to obtain new selective ligands for the CB2 receptor. These compounds, in which the substituents on the naphthalene moiety are varied, have either N -propyl or N -pentyl substituents. A number of these compounds are listed in Table 1, and includes those indoles

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with an unsubstituted naphthalene system (8, JWH-015, 10, JWH-072 and JWH-018, 13, JWH-007), those with a 7methylnaphthoyl group (11 JWH-076, 14, JWH-046 and JWH-048) and those with a 4-methoxynaphthoyl substituent (12, JWH-079 and JWH-081, 15, JWH-094 and JWH-098). Other cannabimimetic indoles summarized in Table 3 include those with 4-alkyl-1-naphthoyl substituents (36 and 37, R'' = CH3, C2H5, C 3H7, C4H9), 7-ethyl-1-naphthoyl substituents (38 and 39), plus 2-methoxy-1-naphthoyl analogs ( 40 and 41), 3-(6-methoxy-1-naphthoyl)indoles (42 and 43), 7-methoxy-1-naphthoyl compounds (44 and 45),

and 4-ethoxy compounds (46 and 47). In all cases R = C3H7 or C 5H11. With few exceptions, the CB 1 receptor affinities for those indoles listed in Table 3 that have a 2-methyl substituent are less than those of the corresponding unsubstituted analog. A notable exception to this generalization is 1-propyl-3-(4methyl-1-naphthoyl)indole (JWH-120, 36, R = C 3H7, R = CH3) and 2-methyl-1-propyl-3-(4-methyl-1-naphthoyl)indole (JWH-148, 36, R = C3H7, R = CH3), which have Ki = 1054 31 nM and Ki = 123 8 nM, respectively. While

Table 3. Receptor Affinities (CB 1 and CB2 ) for Cannabimimetic Indoles 3647 [46]
Compound 36, R = n-Propyl, R = Methyl (JWH-120) 37, R = n-Propyl, R = Methyl (JWH-148) 36, R = n-Pentyl, R = Methyl (JWH-122) 37, R = n-Pentyl, R = Methyl (JWH-149) 36, R = n-Propyl, R = Ethyl (JWH-212) 37, R = n-Propyl, R = Ethyl (JWH-211) 36, R = n-Pentyl, R = Ethyl (JWH-210) 37, R = n-Pentyl, R = Ethyl (JWH-213) 36, R = n-Propyl, R = n-Propyl (JWH-180) 37, R = n-Propyl, R = n-Propyl (JWH-189) 36, R = n-Pentyl, R = n-Propyl (JWH-182) 37, R = n-Pentyl, R = n-Propyl (JWH-181) 36, R = n-Propyl, R = n-Butyl (JWH-239) 37, R = n-Propyl, R = n-Butyl (JWH-241) 36, R = n-Pentyl, R = n-Butyl (JWH-240) 37, R = n-Pentyl, R = n-Butyl (JWH-242) 38, R = n-Propyl (JWH-235) 39, R = n-Propyl (JWH-236) 38, R = n-Pentyl (JWH-234) 39, R = n-Pentyl (JWH-262) 40, R = n-Propyl (JWH-265) 41, R = n-Propyl (JWH-266) 40, R = n-Pentyl (JWH-267) 41, R = n-Pentyl (JWH-268) 42, R = n-Propyl (JWH-163) 43, R = n-Propyl (JWH-151) 42, R = n-Pentyl (JWH-166) 43, R = n-Pentyl (JWH-153) 44, R = n-Propyl (JWH-165) 45, R = n-Propyl (JWH-160) 44, R = n-Pentyl (JWH-164) 45, R = n-Pentyl (JWH-159) 46, R = n-Propyl (JWH-259) 47, R = n-Propyl (JWH-261) 46, R = n-Pentyl (JWH-258) 47, R = n-Pentyl (JWH-260)
a Ref. 44.

Ki (nM) (CB 1 ) 1054 31 123 8 0.69 0.5a 5.0 2.1a 33 0.9 70 0.8 0.46 0.03 1.5 0.2 26 2 52 2 0.65 0.03 1.3 0.1 342 20 147 20 14 1 42 9 338 34 1351 204 8.4 1.8 28 3 3788 323 >10,000 381 16 1379 193 2358 215 >10,000 44 10 250 24 204 26 1568 201 6.6 0.7 45 1 220 29 767 105 4.6 0.6 29 0.4

Ki (nM) (CB 2 ) 6.1 0.7 14 1.0 1.2 1.2 0.73 0.03 10 1.2 12 0.8 0.69 0.01 0.42 0.05 9.6 2.0 12 0.8 1.1 0.1 0.62 0.04 52 6 49 7 7.2 1.3 6.5 0.3 123 34 240 63 3.8 0.6 5.6 0.7 80 13 455 55 7.2 0.14 40 0.6 138 12 30 1.1 1.9 0.08 11 0.5 71 8 441 110 6.9 0.2 10.4 1.4 74 7 221 14 10.5 1.3 25 1.9

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JWH-120 has very little affinity for the CB1 receptor, it has excellent affinity for the CB2 receptor (Ki = 6.1 0.7 nM). This compound is highly selective for the CB 2 receptor with greater than 170-fold selectivity. In the series of indoles with a 4-alkyl substituent (36 and 37, R'' = CH3, C 2H5, C3H7, C 4H9), the CB1 receptor affinities are uniformly very high when the nitrogen substituent is pentyl. The greatest CB1 receptor affinity in this group is JWH-210 (1-pentyl-3-(4ethyl-1-naphthoyl)indole, (36, R = C5H11, R = C2H5) with K i = 0.46 0.03 nM. The 4-propyl (JWH-182, 36, R = C5H11, R = C3H7) and 4-methyl (JWH-122, 36, R = C 5H11, R = CH3) analogs have virtually the same, very high affinity for the CB1 receptor with Ki = 0.65 0.03 nM and Ki = 0.69 0.5 nM, respectively. The N -pentyl compounds with small alkyl groups at C-4 and an indole 2methyl group have CB1 receptor affinities from 1.3 to 1.5 nM. With the exception of the 4-methyl compounds (JWH120 and JWH-148), the N -propyl compounds in this group have relatively high CB 1 receptor affinities with Ki = 2670 nM. The N -pentyl-3-(4-butyl-1-naphthoyl)indoles (36, JWH-240 and 37, JWH-242, R = C 5H11, R = C4H9) have somewhat less affinity for the CB1 receptor than the congeners with smaller alkyl substituents. The N -propyl analogs (JWH-239, 36 and JWH-241, 37, R = C3H7, R = C 4H9), both have very modest affinity for the CB1 receptor with K i = 342 20 nM (36) and Ki = 147 20 nM (37). The CB1 receptor affinities for 7-ethyl analogs 38 and 39 (Table 3) are similar to those of the corresponding 7-methyl compounds (11 and 14, Table 1). However, in contrast to 1propyl-2-methyl-3-(7-methyl-1-naphthoyl)indole (JWH-046, 14, R = C 3H7), which has high affinity for the CB2 receptor (Ki = 16 5 nM) and modest affinity for the CB1 receptor (Ki = 343 38 nM), the corresponding 7-ethyl analog (JWH-239, 39, R = C3H7) has little affinity for either receptor. It had been observed previously that a 4-methoxy-1naphthoyl substituent enhances CB1 receptor affinity, but virtually nothing was known concerning the effect of a
C2H5 O O

methoxy group in other positions of the naphthoyl moiety [37]. In order to gain insight into the effect of methoxy groups at other positions, 1-propyl and 1-pentyl-3-(2methoxy-1-naphthoyl) (4041), 3-(6-methoxy-1-naphthoyl) (4243) and 3-(7-methoxy-1-naphthoyl)indoles (4445) were synthesized and their CB 1 and CB 2 receptor affinities were determined [46]. The CB1 and CB 2 receptor affinities for indoles 4045 are summarized in Table 3. None of the 3-(2-methoxy-1-naphthoyl)indoles (4041, JWH-265 to JWH-268) have appreciable affinity for the CB 1 receptor, with Ki > 380 nM. However, JWH-267 (40, R = C 5H11) and JWH-268 ( 41, R = C 5H11) have high affinity for the CB2 receptor (Ki = 7.2 0.14 nM and Ki = 40 0.6 nM, respectively). 1-Pentyl-3-(2-methoxy-1naphthoyl)indole, JWH-267, is a very highly selective ligand for the CB2 receptor, with greater than 50-fold selectivity over the CB1 receptor. Only one of the 3-(6-methoxy-1-naphthoyl)indoles (4243) has significant affinity for the CB1 receptor. For 1-pentyl3-(6-methoxy-1-naphthoyl)indole (JWH-166, 42, R = C 5H11) K i = 44 10 nM. The other three compounds in this series, JWH-163 (42, R = C3H7), JWH-151 (43, R = C 3H7) and JWH-153 (43, R = C5H11) have Ki > 250 nM. However, all of the compounds in this series have from modest to very high affinity for the CB2 receptor, and JWH151 is a highly selective ligand for the receptor, with Ki = 30 1.1 nM at CB2 with Ki > 10,000 nM at the CB1 receptor. In contrast to the 3-(2-methoxy-1-naphthoyl)- and 3-(6-methoxy-1-naphthoyl)indoles, which in general have at best, very modest affinity for the CB1 receptor, the 1-pentyl3-(7-methoxy-1-naphthoyl)indoles both have high affinity. 1Pentyl-3-(7-methoxy-1-naphthoyl)indole (JWH-164, 44, R = C 5H11), has Ki = 6.6 0.7 nM, while the 2-methyl congener (JWH-159, 45, R = C 5H11), has K i = 45 1 nM. The N -propyl compounds, JWH-165 and JWH-160 (44 and 45, R = C3H7) have little affinity for the CB1 receptor with Ki > 200 nM.

OCH3 O

R''

R'

N 38 R' = H 39 R' = CH3 OCH3

R'

N R

R' 40 R' = H 41 R' = CH3

N R

R 36 R' = H 37 R' = CH3 R'' = CH3, C 2H5, C3H7 or C4H9

H3CO

R' 42 R' = H 43 R' = CH3

N R

R' 44 R' = H 45 R' = CH3

N R

C 2H5O 46 R' = H 47 R' = CH3

R'

N R

Fig. (11). Structures of cannabimimetic indoles with substituted naphthoyl systems. In all cases R = C3 H 7 or C5 H 11 .

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In the course of preparing a series of N -alkyl-3-(4methoxy-1-naphthoyl)indoles (12, R = C3H7 to C7H15), a side reaction occurred which led to the production of the corresponding 3-(4-alkoxy-1-naphthoyl)-N -alkylindoles (48) via an unusual SNAr reaction [47]. The compounds in this series have uniformly poor affinity for the CB1 receptor with Ki > 200 nM. Although indoles 48 with 4-alkoxy substituents of four or more atoms have little affinity for the receptor, N -pentyl cannabimimetic indoles 36 and 37 with alkyl chains of one to four carbon atoms have uniformally high affinity for the CB1 receptor. In order to probe the effect of a 4-alkoxy substituent larger than methoxy, a series of 3(4-ethoxy-1-napthoyl)indoles (46 and 47) was prepared and the CB1 and CB2 receptor affinities were determined (Table 3).
O

the efficacy of these compounds, their ability to stimulate GTP S binding was determined. The results of these determinations are summarized in Table 4. The stimulation is normalized to that produced by 3 M CP-55,940 (2), a maximally effective concentration of this standard cannabinoid agonist. In addition to JWH-120, JWH-151 and JWH-267, the [35S]GTP S binding for JWH-015, 1-propyl2-methyl-3-(1-naphthoyl)indole ( 8), the lead compound for the search for CB2 selective cannabimimetic indoles, was determined, and the data are included in Table 4. As indicated in Table 4, all four of these compounds are potent in the [35S]GTP S assay with EC50 values from 5.1 1.0 nM for JWH-120 ( 36, R = C3H7, R'' = CH3) to 17.7 1.0 nM for JWH-015 (8). One of these CB2 receptor ligands, 1-propyl-2-methyl-3-(6-methoxy-1naphthoyl)indole, JWH-151 (43, R = C3H7) is highly efficacious with an E max of 108.5 13.0% relative to CP55,940. The other three cannabimimetic indoles, 1-propyl-2methyl-3-(1-naphthoyl)indole, JWH-015 (8), 1-propyl-3-(4methyl-1-naphthoyl)indole, JWH-120 ( 36, R = C3H7, R'' = CH3) and 1-pentyl-3-(2-methoxy-1-naphthoyl)indole, JWH267 (40, R = C5H11), are partial agonists relative to CP55,940 with Emax values from 65.7 6.4% (JWH-015) to 78.1 10.7% (JWH-120). The 1-pentyl indoles provide several structural criteria for recognition at the CB1 receptor. As noted previously, CB1 receptor affinity is reduced slightly by the presence of a methyl group at the 2-position of the indole. With the exception of the 1-pentyl-3-(2-methoxy-1-naphthoyl)indoles (JWH-267, 40, R = C5H11), JWH-268, (41, R = C5H11) and 1-pentyl-2-methyl-3-(6-methoxy-1-naphthoyl)indole (JWH-153, 43, R = C5H11), all of the compounds in this series have Ki < 45 nM, indicative of high affinity for the receptor. The addition of a methyl (JWH-122, 36, R = C 5H11, R = CH3, JWH-149, 37, R = C 5H11, R = CH3), ethyl (JWH-210, 36, R = C5H11, R = C2H5, JWH-213, 37, R = C 5H11, R = C 2H5) or propyl (JWH-182, 36, R = C 5H11, R = C3H7, JWH-181, 37, R = C5H11, R = C 3H7) group at C-4 of the naphthalene leads to a considerable increase in CB1 receptor affinity, however, a butyl group at C-4 (JWH-240, 36 , R = C 5H11, R = C4H9, JWH-242, 37, R = C5H11, R = C4H9) results in a slight decrease in affinity (Table 3). Neither a 7-methyl-1-naphthoyl (JWH-048, 14, R = C5H11, Table 1) nor a 7-ethyl-1naphthoyl (JWH-234, JWH-262, 39, R = C5H11, Table 3) substituent has a significant effect on affinity for the CB1 receptor In the N -pentyl series, a 2-methoxy-1-naphthoyl substituent (JWH-267, 40, R = C5H11, JWH-268, 41, R =

RO

N R 48 R = n-propyl to n-heptyl

Fig. (12). Structure of 4-alkoxy-1-naphthoylindoles.

Indoles 46 and 47 have weaker affinities for the CB1 receptor than the corresponding methoxy analogs (12 and 15, Table 1). However they follow the usual trend in that the N propyl indoles (JWH-259, 46, R = C 3H7 and JWH-261, 47, R = C3H7) have significantly less affinity for the receptor than the N -pentyl compounds. Neither N -propyl analog has a CB 1 receptor affinity better than 220 nM (JWH-259). 1Pentyl-3-(4-ethoxy-1-naphthoyl)indole (JWH-258, 46, R = C 5H11) has very high affinity for the CB1 receptor with Ki = 4.6 0.6 nM, however, this is somewhat less than that for the 4-methoxy analog (JWH-081, 12, R = C5H11, Ki = 1.2 0.1 nM). The 2-methyl compound (JWH-260, 47, R = C 5H11) has Ki = 29 0.4 nM which is considerably less than that of the 2-methyl-1-pentyl-3-(4-methoxy-1naphthoyl)indole (JWH-098, 15, R = C 5H11) with Ki = 4.5 0.1 nM. A particularly significant result of this study of cannabimimetic indoles is the discovery of three new highly selective ligands for the CB2 receptor [44]. These compounds are 1-propyl-3-(4-methyl-1-naphthoyl)indole, JWH-120 (36, R = C3H7, R'' = CH3), which is 173-fold selective, 1-pentyl-3-(2-methoxy-1-naphthoyl)indole, JWH267 (40, R = C5H11), 53-fold selective, and 1-propyl-2methyl-3-(6-methoxy-1-naphthoyl)indole, JWH-151 (43, R = C 3H7), which is >333 fold selective. In order to evaluate
Table 4.

EC 50 and Emax Values (mean SEM) for GTP S Binding of CB2 for Selective Ligands. Assays were carried out in Human CB 2 Receptor-Expressing CHO Cells. Emax Values are Reported as Per Cent Relative to 3 M CP-55,940 (2)
Compound 8, (JWH-015) 36, R = C3 H7 , R'' = CH3 (JWH-120) 40, R = C5 H11 (JWH-267) 43, R = C3 H7 (JWH-151) EC50 (nM) 17.7 1.0 5.1 1.6 4.9 0.8 12.0 2.9 Emax (% CP-55940) 65.7 6.4 78.1 10.7 67.3 2.9 108.5 13.0

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C 5H11, Table 3) effectively destroys affinity for the CB1 receptor, while a 4-methoxy group (JWH-081, 12, R = C 5H11, JWH-098, 15, R = C5H11, Table 1) slightly increases affinity relative to the unsubstitued analogs. Replacing the 4-methoxy group with a 4-ethoxy (JWH-258, 46, R = C5H11, JWH-260, 47, R = C 5H11, Table 3) diminishes CB1 affinity somewhat. A 6-methoxy-1naphthoyl substituent decreases affinity for the CB1 receptor in the compound unsubstitued at C-2 of the indole nucleus (JWH-166, 42, R = C 5H11, Table 3); while the 2-methyl analog (JWH-153, 43, R = C5H11,) has little affinity. In contrast, the 7-methoxy analogs (JWH-164, 44, R = C5H11, and JWH-159, 45, R = C5H11), have receptor affinities comparable to those of the 4-ethoxy compounds (Table 3). In general, cannabimimietic indoles with N -propyl substituents have significantly less affinity for the CB1 receptor than the corresponding N -pentyl compounds. Although a methyl group at C-2 of the indole usually attenuates CB1 receptor affinity somewhat, in the case of the compounds with an unsubstituted naphthoyl group (JWH015, 8, JWH-072, 10, R = C3H7) and the 4-methyl-1naphthoyl analogs (JWH-120, 36, R = C3H7, R = CH3 and JWH-148, 37, R = C3H7, R = CH3), the 2-methyl compounds have considerably greater CB1 receptor affinities than the unsubstituted compounds (Tables 1 and 3). The situation is similar for the 1-propyl-3-(4-butyl-1naphthoyl)indoles (JWH-239, 36, R = C3H7, R = C4H9 and JWH-241, 37, R = C 3H7, R = C 4H9). However, the 2methyl analog (JWH-241) has only slightly more than twofold greater affinity for the CB1 receptor than JWH-239. With the exception of the 4-ethyl- (JWH-211, JWH-212), and 4-propyl-1-naphthoylindoles (JWH-180, JWH-189), none of the N -propyl-3-(4-alkyl-1-naphthoylindoles) has a CB 1 receptor affinity of less than 100 nM. In the N -pentyl series, the 4-propyl-1-naphthoylindoles (JWH-182, JWH181) have exceptionally high affinity for the CB1 receptor, respectively (Table 3). These high affinities are reflected in the N -propyl analogs; JWH-180 (36, R = C3H7, R = C 3H7) has K i = 26 2 nM and JWH-189 (36, R = C3H7) has Ki = 70 0.8 nM. In the methoxynaphthoyl series (Tables 1 and 3), the relative magnitudes of the CB1 receptor affinities for the N -propyl indoles parallel those of the N pentyl analogs. However, the compounds in this series have little affinity for the CB1 receptor with affinities from 204 nM, to >10,000 nM with the exception of JWH-079 (12, R = C 3H7), which has K i = 63 3 nM. To gain insight into the receptor interactions responsible for the SAR of these cannabimimetic indoles at the CB1 receptor, molecular modeling and receptor docking studies were carried out. These studies were similar to those described above for naphthoylindoles JWH-018 (10, R = C 5H11), JWH-122 ( 27) and JWH-081 ( 12, R = C 5H11) [44]. The set of 3-(4-propyl-1-naphthoyl)indoles (JWH-180, 36, R = C3H7, R = C3H7, JWH-189, 37, R = C3H7, R = C 3H7, JWH-182, 36, R = C5H11, R = C 3H7, JWH-181, 37, R = C5H11, R = C3H7 Table 3) and the set of 3-(6methoxy-1-naphthoyl)indoles (JWH-163, 42, R = C3H7, JWH-151, 43, R = C 3H7, JWH-166, 42, R = C 5H11, JWH153, 43, R = C 5H11 Table 3) were chosen. In addition, the N -pentyl-3-(2-methoxy-1-naphthoyl)indoles (JWH-267, 40, R = C5H11 and JWH-268, 41, R = C5H11, Table 3) were examined.

1-Pentyl-3-(4-propyl-1-naphthoyl)indole (36, R = C 5H11, R = C 3H7) is a very high affinity CB1 receptor ligand (K i = 0.65 0.03 nM, Table 3), and it was docked in the same position as JWH-018 (10, R = C5H11), JWH-122 (27) and JWH-081 (12, R = C5H11) [44]. These docking studies showed that the N-pentyl tail of JWH-182 extends over a phenylalanine on helix-3 of the CB 1 receptor, and the indole moiety is between transmembrane helices 5 and 6. The naphthoyl ring is intracellular to a tryptophan on helix-5 and another on helix-6 , with the 4-propyl substituent on the naphthyl ring situated in an open area within the binding pocket. In this position, both the indole and naphthoyl rings have stacking interactions with the tryptophans, and the carbonyl oxygen forms a weak hydrogen-bond with the tryptophan on helix-6. Using the docking position employed for JWH-182, the consequences of substitution at other positions on the naphthoyl ring were explored. Substitution at the 2naphthoyl position as in 1-pentyl-3-(2-methoxy-1naphthoyl)indole (JWH-267, 40, R = C5H11, Table 3) causes a large decrease in affinity, relative to the 4-propyl-1naphthoyl analog (JWH-182). Docking studies show that the 2-methoxy group in JWH-267 has severe steric conflicts with the tryptophan on helix-6, causing the ligand to lose most of its aromatic stacking interactions. Similar docking studies indicated that various substituents can be placed at C-4 of the naphthoyl moiety, and do not cause a significant decrease in affinity, because there is a fairly wide and deep lipophilic binding pocket in this region of the receptor. However, substitution at C-6 results in diminished affinity for 1-pentyl-3-(6-methoxy-1naphthoyl)indole (JWH-166, 40, R = C5H11, Table 3) relative to the 4-propyl-1-naphthoyl analog (JWH-182, 36, R = C 5H11, R = C 3H7). In its lowest energy conformation, a methoxy substituent at C-6 has some steric conflicts with two amino acids that are alleviated by rotation of the methoxy group out of the plane of the naphthoyl ring into a higher energy rotameric state. The necessity for the methoxy group to assume a higher energy conformation in order to be accommodated at the binding site, may contribute to the reduced CB1 affinity of JWH-166 relative to JWH-182. Substitution at C-7 of the naphthoyl ring results in only a slight reduction in affinity for 1-pentyl-3-(7-methoxy-1naphthoyl)indole (JWH-164, 44, R = C5H11, Table 3). Docking studies show that a methoxy substituent at C-7 encounters no steric problems in its minimum energy conformation. However, the methoxy group blocks the aromatic stacking interaction between the naphthoyl ring and the tryptophan on helix-5, which is present in the 4-propyl analog. This loss of an aromatic stacking interaction may account for the 10-fold reduction in affinity of the 7-methoxy compound (JWH-164, 44, R = C5H11) relative to the 4propyl analog (JWH-182, 36, R = C 5H11, R = C 3H7). Based on a study of rigid naphthylidene-substituted aminoalkylindene analogs of cannabimimetic indoles that mimic the s-cis or s-trans conformation of the cannabimimetic indoles, it was concluded that that the strans conformation is probably the preferred conformation for the interaction of cannabimimetic indoles at both the CB1 and CB 2 receptors [16]. For this reason, the lowest energy strans conformer of 2-methyl-1-pentyl-3-(4-propyl-1-

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I N CH3 N NO2

CH3

OCH3

49

50

Fig. (13). Structures of AM1241 and AM630.

naphthoyl)indole (JWH-181, 37, R = C 5H11, R = C 3H7).), rather than its global minimum energy s-cis conformer was used in the docking studies. Because of the use of the s-trans conformer as the bioactive conformation for the C-2 methyl indoles, the affinities of ligands in this series can, in general, be expected to be reduced relative to those of the corresponding indoles without a C-2 methyl group for which the global minimum energy conformers are s-trans conformers. Such a general reduction is, in fact, seen in this series (Tables 1 and 3). Compared to their N -pentyl congeners, each analog in the N -propyl series shows reduced CB1 receptor affinity. In the N -pentyl series, the pentyl tail resides in a hydrophobic binding pocket which appears to orient the aromatic rings of the ligand for aromatic stacking interactions with the receptor. The N -propyl tail is too short to access this hydrophobic pocket and simultaneously allow the ligand to engage in aromatic stacking interactions. As a result, ligands with the propyl substituent may have more difficulty in assuming the correct aromatic region orientation necessary for productive binding at the CB1 receptor. The importance of an alkyl chain of certain length is very reminiscent of the classical cannabinoids for which it has been shown that C-3 alkyl chains shorter than pentyl have severely reduced CB1 affinities [2-5]. In addition to the new cannabimimetic indoles reported by the Clemson group, several other new compounds have been described, some of which are very promising, highly selective ligands for the CB2 receptor. One indole derivative, AM1241, (2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2ylmethyl)-1H-indol-3-yl]methanone (49) with K i = 3.4 0.5 nM at the CB 2 receptor and Ki = 280 41 nM at the CB1

receptor has 82-fold selectivity for the CB 2 receptor [48]. This compound has been found to produce antinociception to thermal stimuli, an effect which is blocked by the CB2 receptor antagonist AM630 (50) [48, 49]. In another study it was found that the antihyperalgesic and antialloldynic effects of AM1241 were blocked by the CB2 antagonist SR144528, but not by the CB1 antagonist SR141716 [50]. These data indicate that these effects are mediated through the CB 2 receptor. Similar effects were noted in capsaicin induced hyperalgesia and aalodynia [51]. Very recently, a group at Bristol-Myers Squibb has described two new groups of indole based cannabinoids. One series of compounds was comprised of amides derived from a substituted indole 3-carboxylic acid, several of which show selectivity for the CB2 receptor [52]. The most highly selective compound in this series is phenylalanine derived amide 51, which has excellent affinity for the CB2 receptor (Ki = 8 nM) and little affinity for the CB1 receptor (Ki = 4000 nM). The second series of cannabimimetic indoles are pyridones, derived from compounds similar to 51 [53]. One of these indolopyridones (52) has very high affinity for the CB 2 receptor (Ki = 1.0 0.2 nM), and also has high affinity for the CB1 receptor (Ki = 16 4 nM). In addition, indolopyridone 52 is orally effective in a mouse model of inflammation. Two studies of the in vitro metabolism of cannabimimetic indoles have been carried out by Zhang et al. [54, 55]. Both of these studies employed rat liver microsomes, and the metabolites were characterized by a combination of mass spectrometry and NMR spectroscopy. In the initial study, WIN-55,212-2 (4) provides two major and at least six minor metabolites [54]. The major
H3C

O N N OCH3 N CH3 H

CO2CH3

O N N OCH3 N

CH3 CH3

O 51 52

Fig. (14). Bristol-Myers Squibb cannabimimetic indoles.

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SOCH3 N CH3 F CO2H 53 54 H3CO CO2H CH3

Cl

N 55 O

Fig (15). Structures of sulindac, indomethacin, and cannabimimetic indenes.

metabolites are dihydrodiols, derived by arene oxidation of the naphthalene ring of 4 [56]. The major metabolites were the only compounds present in sufficient quantity for NMR studies, the other metabolites were characterized only by mass spectrometry. The minor products included two monohydroxy compounds and metabolites derived by oxidation of the morpholine ring. The second study was an investigation of the metabolism of AM630 (50), in which the metabolites were characterized by mass spectrometry [55]. A total of 17 metabolites were identified, which included cleavage of the methyl ether, aromatic hydroxylation and a variety of products resulting from oxidation of the morpholine ring, with and without ether cleavage.

nM). The CB1 receptor affinities of the corresponding Z isomers are significantly lower. Careful preparation of the pure E- (7) and Z-isomers of 4[2-[1-(1-naphthalenylmethylene)-1H-inden-3-yl]ethyl]morpholine and 4-[2-[2-methyl-1-(1-naphthalenylmethylene)-1Hinden-3-yl]ethyl]morpholine by Reggio et al. afforded an opportunity to study which stereoisomer was responsible for biological activity [16]. The compounds described by Reggio's group were carefully purified by chromatography, and the structures assigned by 1H NMR techniques, primarily NOE experiments. Molecular modeling studies demonstrated that the naphthyl group of WIN-55212-2 and the p-methoxyphenyl group of pravadoline occupied the same region of space. Comparison of WIN-55212-2 with the indenes indicated that only a small amount of energy was required to overlay the naphthyl rings of the two classes of ligands. These studies support the appropriateness of using these rigid analogs as models for the s-cis and s-trans conformers of cannabimimetic indoles. The E isomers were found to have high affinity for both receptor subtypes, whereas the Z -isomers exhibit poor affinity. Since the Eisomers of the indenes are a model for the s-trans conformer of the indoles, this evidence suggests that s-trans is the bioactive conformation. Studies involving mutant receptors and molecular modeling strongly suggest that cannabimimetic indoles interact with the cannabinoid receptors primarily through aromatic stacking [39, 40, 43]. The importance of aromatic group orientation in the indene series supports this hypothesis and implies that the indenes interact with the CB 1 receptor through the same mechanism as the indoles [16]. In order to exclude a possible hydrogen-bonding mechanism of these ligands with the receptor, a series of indenes was prepared with an alkyl group in place of the ethylmorpholino found in 7 and 55. [44 and R. Mabon, unpublished work]. The affinities of several of these compounds as mixtures of E- and Z- isomers for the CB1 receptor were determined

R1 R 56-59

Fig. (16). Structures of Indenes 56-59.

INDENES Cannabimimetic indenes were first prepared by the Sterling-Winthrop group, while studying the effects of pravadoline (3) on the central nervous system [15]. It was observed that sulindac (53), an indene analog of indomethacin, (54), has anti-inflammatory activity comparable to that of indomethacin, but lacks the CNS side effects of 54. Several 1-(2-(4-morpholino)ethyl)-3-arylidene derivatives were prepared as mixtures of E and Z isomers. Derivatives in which the appended aryl group was a substituted phenyl ring, exhibited low affinities. Two Enaphthylidene analogs, (55), showed good affinity (Ar = 1naphthyl, IC50 = 1.0 nM; 4-methoxy-1-naphthyl, IC50 = 0.9
Table 5.

Receptor Affinities of Indenes Tested as Mixtures of E and Z Stereoisomers

Compound JWH-171, 56 JWH-170, 57 JWH-173, 58 JWH-172, 59 R pentyl propyl pentyl propyl R1 H H CH3 CH3 Ki (nM) CB 1 51 2 698 27 108 12 140 8

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Ar N R

R5

N R1

R2

60-64

65-70

71-84

Fig. (17). Structures of Cannabimimetic Pyrroles.

and are shown in Table 5. The introduction of a pentyl group (56, JWH-171) afforded a mixture of E and Z isomers that showed good affinity (Ki = 51 2 nM) for the CB1 receptor, however, this is somewhat less than that of indene 7. The E-isomer of 56 (35, JWH-176) shows increased affinity for the CB1 receptor, with Ki = 26 4 nM. [44] The introduction of a propyl group in JWH-170 (57) results in significantly attenuated CB1 affinity, a trend which has been seen repeatedly in the indole series. The presence of a 2methyl substituent results in reduced CB1 affinity for the pentyl compound (58, JWH-173), but increased affinity for

determined that the benzene moiety of the indole was not necessary for biological activity [13]. Since it appeared possible that these pyrrole derivates would show cannabimimetic activity, the synthesis of a series of alkyl pyrroles (6) analogous to previously prepared indoles was undertaken. These compounds showed reduced affinity relative to their indole counterparts, but demonstrated a similar trend with regard to the N -alkyl chain length, where CB 1 receptor affinity peaks at around five carbons. 3-(1Naphthoyl)-N -pentylpyrrole is relatively potent in the spontaneous activity and tail flick assays, and causes a dose-

Table 6. Receptor Affinities of 2-Phenyl-4-(1-naphthoyl)-N-alkylpyrroles

Compound JWH-156, 60 JWH-150, 61 JWH-145, 62 JWH-147, 63 JWH-146, 64 R propyl butyl pentyl hexyl heptyl Ki (nM) CB 1 890 364 59.7 1.0 11.6 9.4 19.0

the propyl compound (59, JWH-172) relative to JWH-171 (56). PYRROLES Based on the alignment proposed by Huffman et al.[12], in which the ketonic carbonyl of WIN-55212-2 (4) and the phenolic hydroxyl of THC (1) are overlaid, as are the naphthalene moiety of 4 and the A-ring of 1, it was

dependent inhibition of electrically evoked contractions of the mouse vas deferens that could be antagonized by SR141716 [13, 57]. Based upon the hypothesis that cannabimimetic indoles, and thus the corresponding pyrroles, interact with the receptor largely through aromatic stacking, a series of 2phenyl-4-(1-naphthoyl)-N alkyl pyrroles (60-64) was synthesized. With the exception of the N -propyl derivative (JWH-156, 60), these compounds exhibited good affinity for

Table 7. Receptor Affinities 2-Aryl-4-(1-naphthoyl)-N-pentyl pyrroles, 65-70

Compound JWH-309, 65 JWH-347, 66 JWH-243, 67 JWH-292, 68 JWH-308, 69 JWH-307, 70 Aryl 1-naphthyl 2-naphthyl p-methoxyphenyl o-methoxyphenyl p-fluorophenyl o-fluorophenyl Ki (nM) CB 1 40.83 3.32 333.7 17.0 285 40.3 29 0.7 41 1.4 7.7 1.8

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Table 8.

CB 1 and CB2 Affinities of pyrroles 71-84

R1 R2 R3 R4 R5 Affinity Ki (nM) rCB1 hCB2 552 314 9.85 2.1 309.7 20.8 55.6 26.5 6.8 1.0 691.3 101.3 194.5 27.5 139 55 >1000 >1000 >1000 >10000 >1000 483.5 211

Compound

71 72 73
74

C5 H11 C5 H11 C3 H7 pClC6 H4 CH2 C5 H11 C3 H7 pClC6 H4 CH2 C5 H11 C5 H11 C5 H11 pClC6 H4 CH2 C5 H11 C5 H11 C5 H11

H CH3 CH3 CH3 CH3 CH3 CH3 H CH3 CH3 CH3 CH3 CH3 CH3

1-naphthyl 1-naphthyl 1-naphthyl 1-naphthyl 1-naphthyl 1-naphthyl 1-naphthyl 1-naphthyl C6 H5 C6 H5 C6 H5 HO(CH 2 ) 3 o(CH3 CO)C6 H4 NH c- C6 H11 NH

H H H H Br Br Br

H CH3 CH3 CH3 CH3 CH3 CH3 (CH2 ) 4

30.5 4.7 45.3 7.5 >1000 83.7 17.8 13.3 0.5 780 326 38 7.2 235.8 6.2 >1000 >1000 >1000 >3000 367.3 31.2 415.5 79.5

75 76 77 78 79 80 81 82 83 84

H Br H H H H

CH3 CH3 CH3 CH3 CH3 CH3

the CB1 receptor (Table 6). Retaining the pentyl group, several analogs of JWH-145 (62) with substituted phenyl substituents (65-70) have been prepared, and their receptor affinities have been determined (Table 7). These compounds exhibit a range of affinities for the CB1 receptor, with some compounds exhibiting affinities similar to that of 62, and others displaying little or no affinity. Initial results indicate that para-substituents provide decreased receptor affinity when compared with 62. This appears to be the case, regardless of the electronic nature of the substituent, although there is not enough evidence to rule out electronic effects. Increase in substituent size from fluoro to methoxy results in a rapid decline of affinity. In both the ortho and para positions, higher receptor affinity is provided by the smaller fluoro substituent with the difference more pronounced in the para position. This trend is observed with 2-(1-naphthyl) and 2-(2-naphthyl)pyrrole substituents. The 2-naphthyl substituent has one ring oriented such that it is equivalent to a meta and para substituent on the aryl ring attached to the pyrrole. Thus, the 2-naphthyl compound, (66), has a significantly lower affinity for the CB1 receptor than the pyrrole with a 1-naphthyl substituent at C-2, (61). Due to the relatively high affinity displayed by the hybrid cannabinoid JWH-161 (20) [42] pyrrole derivatives with other substituents appended to the pyrrole nucleus have been synthesized [58]. Replacement of the naphthoyl ring system resulted in decreased affinity for the CB1 and CB2 receptors, shown in Table 8. The presence of a benzoyl substituent at C-3 gives compounds 79-81, which have no appreciable affinity for either the CB1 or CB 2 receptor. Two compounds, 83 and 84, with carboxamido groups at C-3, were also prepared. It was predicted that the carboxamido group would occupy the same spatial location as the naphthyl ring of the 8 cannabimimetic indoles or the cyclohexene ring of -THC.

These compounds also show little affinity for either receptor, although their affinities are somewhat enhanced relative to pyrroles 79-81. Replacement of the C-3 aromatic system with a 3-hydroxypropane (82) in an attempt to mimic the northern aliphatic hydroxyl of some successful traditional cannabinoids results in a complete loss of affinity [58]. Substitution of both -positions of the pyrrole with methyl groups has little effect on affinity for either receptor, and the introduction of a bromine atom to the unsubstituted position results in a slight increase in binding for both receptor subtypes. The addition of a cyclohexyl ring (78) connecting the 4- and 5-positions greatly reduces affinity, although it is assumed that the substituent occupies the same location as the benzenoid moiety of the corresponding indoles. CONCLUSION Modeling studies of the receptor and results obtained with mutant CB1 receptors strongly suggest that cannabimimetic indoles, and presumably the pyrroles and indenes, interact at a different site in the receptor than traditional cannabinoids and endogenous cannabinoids, such as anandamide. These studies also indicate that these classes of cannabinoid receptor ligands interact with the CB1, and probably the CB 2 receptor, primarily by aromatic stacking interactions. These interactions with the CB 1 receptor are considerably different than those of the traditional cannabinoids, and it now appears unlikely that it will be possible to develop a universal pharmacophore for the cannabimimetic indoles and the traditional cannabinoids. The experiments with mutant CB1 receptors combined with modeling studies have shed considerable light on the nature of the interactions of various classes of cannabinoids with the

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Huffman and Padgett Bell, M. R.; D'Ambra, T. E.; Kumar, V.; Eissanstat, M. A.; Herrmann, J. L.; Wetzel, J. R.; Rosi, D.; Philion, R. E.; Daum, S. J.; Hlasta, D. J.; Kullnig, R. K.; Ackerman, J. H.; Haubrich, D. R.; Luttinger, D. A.; Baizman, E. R.; Miller, M. S.; Ward, S. J. J. Med. Chem . 1991, 34, 1099. D'Ambra, T. E.; Estep, K. G.; Bell, M. R.; Eissenstat, M. A.; Josef, K. A.; Ward, J.; Haycock, D. A.; Baizman, E. R.; Casiano, F. M.; Beglin, N. C.; Chippari, S. M.; Grego, J. D.; Kullnig, R. K.; Daley, G. T. J. Med. Chem. 1992, 35, 124. Huffman, J. W.; Dai, D.; Martin, B. R.; Martin, B. R.; Compton, D. R. Bioorg. Med. Chem. Lett. 1994, 4, 563. Lainton, J. A. H.; Huffman, J. W.; Martin, B. R.; Compton, D. R. Tetrahedron Lett. 1995, 36, 1401. Wiley, J. L.; Compton, D. R.; Dai, D.; Lainton, J. A. H.; Phillips, M.; Huffman, J. W.; Martin, B. R. J. Pharmacol. Exp. Ther. 1998, 285, 995. Kumar, V.; Alexander, M. D.; Bell, M. R; Eissenstat, M. A.; Casiano, F. M.; Chippari, S. M.; Haycock, D. A.; Luttinger, D. A.; Kuster, J. E.; Miller, M. S.; Stevenson, J. I.; Ward, S. J. Bioorg. Med. Chem. Lett. 1995, 5, 381. Reggio, P. H.; Basu-Dutt, S.; Barnett-Norris, J.; Castro, M. T.; Hurst, D. P.; Seltzman, H. H.; Roche, M. J.; Gilliam, A. F.; Thomas, B. F.; Stevenson, L. A.; Pertwee, R. G.; Abood, M. E. J. Med. Chem. 1998, 41, 5177. Huffman, J. W. Curr. Med. Chem. 1999, 6, 705. Devane, W. A.; Dysarz, F. A.; Johnson, M. R.; Melvin, L. S.; Howlett, A. C. Mol. Pharmacol. 1988, 34, 605. Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.; Bonner, T. H. Nature 1990, 346, 561. Grard, C. M.; Mollereau, C.; Vassart. G.; Parmentier, M. Biochem. J. 1991, 279, 129. Little, P. J.; Compton, D. R.; Johnson, M. R.; Melvin, L. S.; Martin, B. R. J. Pharmacol. Exp. Ther. 1988, 247, 1046. Compton, D. R.; Rice, K. C.; De Costa, B. R.; Razdan, R. K.; Melvin, L. S.; Johnson, M. R.; Martin, B. R. J. Pharmacol Exp. Ther. 1993, 265, 218. Munro, S.; Thomas. K. L.; Abu-Shar, M. Nature 1993, 365, 61. Pertwee, R. G. Pharmacol. Ther. 1997, 74, 129. Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood, M. E. J. Pharmacol. Exp. Ther. 1996, 278, 989 Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.; Mackie, K.; Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R. L. Mol.Pharmacol . 1995, 48, 443. Busch-Petersen, J.; Hill, W. A.; Fan, P.; Khanolkar, A.; Xie, X.Q.; Tius, M. A.; Makriyannis, A. J. Med. Chem. 1996, 39, 3790. Pertwee, R. G. Gen. Pharmacol. 1993, 24, 811. Selley, D. E.; Stark, S.; Sim, L. J.; Childers, S. R. Life Sci. 1996, 59, 659. Howlett, A. C.; Barth, F.; Bonner, T. I.; Cabral, G.; Casellas, W. A.; Devane, W. A.; Felder, C. C.; Herekenham, M.; Mackie, K.; Martin, B. R.; Mechoulam, R.; Pertwee, R. G. Pharmacol. Rev. 2002, 54, 161. Eissenstat, M. A.; Bell, M. R.; DAmbra, T. E.; Alexander, E. J.; Daum, S. J.; Ackerman, J. H.; Gruett, M.D.; Kumar, V.; Estep, K. G.; Olefirowicz, E. M.; Wetzel, J. R.; Alexander, M. D.; Weaver, J. D.; Haycock, D. A.; Luttinger, D. A.; Casiano, F. M.; Chippari, S. M.; Kuster, J. E.; Stevenson, J. I.; Ward, S. J. J. Med. Chem. 1995, 3094. Kuster, J. E.; Stevenson, J. I.; Ward, S. J.; DAmbra, T. E.; Haycock, D. A. J. Pharmacol. Exp. Ther. 1993, 264, 1352. Compton, D. R.; Gold, L. H.; Ward, S. J.; Balster, R. L.; Martin, B. R. J. Pharmacol. Exp. Ther. 1992, 263, 1118. D'Ambra, T. E.; Eissenstat, M. A.; Abt, J.; Ackerman, J. H.; Bacon, E. R.; Carabateas, P. M.; Josef, K. A.; Kumar, V.; Weaver, J. D.; Arnold, R.; Casiano, F. M.; Chippari, S. M.; Haycock, D. A.; Kuster, J. E.; Luttinger, D. A.; Stevenson, J. I.; Ward, S. J.; Hill, W. A.; Khanolkar, A.; Makriyannis, A. Bioorg. Med. Chem. Lett. 1996, 6, 17. Shim, J.-Y.; Collantes, E. R.; Welsh, W. J.; Subramaniam, B.; Howlett, A. C.; Eissenstat, M. A.; Ward, S. J. J. Med. Chem. 1998, 41, 4521. Huffman, J. W.; Wu, M.-J.; Lainton, J. A. H.; Dai, D.; Phillips, M.; Keel, C.; Wiley, J. L.; Compton, D. R.; Showalter, V.; Abood, M. E.; Martin, B. R. 1997 Symposium on the Cannabinoids International Cannabinoid Research Society; Burlington, VT, 1997, p. 8.

CB 1 receptor, and in the future should assist in providing a firm basis for the continued development of the SAR of both classical and indole based cannabinoids. Although much has been accomplished in developing the medicinal chemistry of the cannabimimetic indoles, pyrroles and indenes in the nearly 15 years that the biological activity of these compounds has been recognized, a great deal remains to be done. Inter alia , these include further study of the SAR of the indenes and pyrroles, which should shed additional light upon the detailed interactions of these ligands with the cannabinoid receptors. Also, the development of additional ligands which are highly specific for each receptor should be carried out in order to develop further insight into the physiological role of each receptor, and with the ultimate goal of developing clinically useful compounds. In the past few years, the significance of the CB 2 receptor has become apparent, and it will be necessary to identify additional ligands that show a high degree of affinity for CB2 relative to CB1. The in vivo pharmacology of such selective agonists should be informative in terms of ultimately identifying the role of endogenous cannabinoids in animal physiology. Finally, although a great deal of work has been carried out concerning the SAR of the cannabimimetic indoles, additional systematic studies of the effects of various substituents on the indole nitrogen and ring carbons, as well as on the naphthalene ring need to be carried out. ACKNOWLEDGEMENTS The author thanks Dr. Patricia H. Reggio of the University of North Carolina at Greensboro for many helpful discussions over a several year period. The work carried out at Clemson University which is included in the review was supported by grants DA03590 and DA15340 to JWH and DA15579 to LWP, all from the National Institute on Drug Abuse. The author also thanks Drs. Billy R. Martin, Jenny L. Wiley, David R. Compton, Dana E. Selley and Mary E. Abood of Virginia Commonwealth University for the pharmacological evaluation of the compounds prepared in our laboratory. Thanks is also extended to the graduate students and postdoctorals at Clemson University who carried out the work from our group described in this review. REFERENCES
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