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Med Chem Res (2012) 21:2571–2578
DOI 10.1007/s00044-011-9781-3
ORIGINAL RESEARCH
Theoretical study on some non-selective beta-adrenergic
antagonists and correlation to their biologically active
configurations
Ahmad Reza Bekhradnia •
Mohammad Ali Ebrahimzadeh
Received: 3 December 2010 / Accepted: 4 August 2011 / Published online: 20 August 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The non-selective classification refers to those
beta-blockers capable of blocking both b1 and b2 receptors
with equivalent efficacy. All of these beta-blockers consist
of an aryloxypropanolamine side chain linked to an aro-
matic or heteroaromatic ring. Each of these drugs possesses
at least one chiral center, and high degree of enantiose-
lectivity in binding to beta-adrenergic receptor. In this
research, ab initio method with 6-31G* basis set was
employed for investigation of correlation between opti-
mized geometry and biologically active configuration
on both enantiomers of Timolol, Nadolol, Bunolol, and
Propranolol. These calculations show higher stabilities for
(S)-enantiomer compared with (R)-antipode, for each ste-
reoisomer. Also, torsion angles around the N2C3C4O5 bond
confirm that (S)- and (R)-Propranolol have the lowest and
highest dihedral angles related to other non-selective beta-
blockers, respectively. Furthermore, the (S)-enantiomers of
beta-blockers reveal the more negative natural charges for
oxygen atom in hydroxyl as well as nitrogen atom in
aryloxypropanolamine group than related (R)-enantiomer.
Keywords Non-selective beta-adrenergic antagonists

Ab initio method
Geometrical optimization

Thermodynamic data
A. R. Bekhradnia
M. A. Ebrahimzadeh (&)
Pharmaceutical Sciences Research Center, Department of
Medicinal Chemistry, Mazandaran University of Medical
Sciences, Sari, Iran
e-mail: reza_bnia@yahoo.com; zadeh20@yahoo.com
A. R. Bekhradnia
e-mail: abekhradnia@mazums.ac.ir
MEDICINAL
CHEMISTRY
RESEARCH
Introduction
In clinical practice, the beta-adrenergic antagonists are an
important class of drugs due to their high prevalence of
use. They are commonly employed in the treatment of
conditions including hypertension, cardiac arrhythmia,
angina pectoris, tremor, anxiety, migraine and hyperthy-
roidism and also topically for open angle glaucoma (Hor-
inouchi et al., 2009; Kadam and Kompella, 2009; Baker,
2005). Beta-blockers are normally distinguished based on
their selectivity for beta-receptors. The non-selective beta-
blockers, such as Timolol, Nadolol, Bunolol, and Pro-
pranolol antagonize both b1 and b2 adrenergic receptors.
Selective antagonists, such as metoprolol, atenolol, and
acebutolol have much greater binding affinity for the b1
adrenergic receptors. The selective beta-blockers are nor-
mally indicated for patients in whom b2 receptor antago-
nism might be associated with an increased risk of adverse
effects. Such patients include those with asthma or diabetes
or patients with peripheral vascular disease or Raynaud’s
disease (Baker, 2005; Smith and Teitler, 1999; Mehvar and
Brocks, 2001).
A common feature in the chemical structure of beta-
blockers has been depicted in Fig. 1. These consist of an
aromatic or heteroaromatic ring linked to an oxygen atom
which is bound to a propanol side chain linked to an amine.
There is at least one aromatic ring structure attached to a
side alkyl chain possessing a secondary hydroxyl and
amine functional group which is a secondary amine and its
N-substituent is either an isopropyl or tertiary butyl group
which affords optimal affinity and some selectivity for b
over a receptors.
In comparing with ethanolamine fragments, it might
appear that lengthening the side chain of propanolamine
would prevent appropriate binding of the required
123
2572
Propanol
Oxy H
Aryl Amine
HO H The intent of this work is a theoretical study to find out
N
O some correlation between their structure and biological
R
Ar
Fig. 1 General beta-blocker structure (aryloxypropanolamines)
functional groups to the same receptor site. Nevertheless,
molecular models illustrate that the side chains of aryl-
oxypropanolamines can approve a conformation that places
the hydroxyl and amine groups into approximately the
identical position in space. The aryloxypropanolamine are
more potent beta-blockers than the related arylethanolam-
ines and the beta-blockers currently consumed clinically
are aryloxypropanolamines.
For all of beta-blockers, the amino group is important
because the amine is a main site of drug metabolism and so
drug inactivation. Also, this functional group causes the
compounds which are predominantly ionized at physio-
logic pH and protonated amine group is required for b
receptor binding. Evidently, the biological activity is
affected by propanolamine segment. Nearly all of these b
blockers consist of an aryloxypropanolamine side chain
linked to an aromatic or heteroatom ring which is ortho-
substituted. Generally, heteroaromatic one (e.g., pindolo-
land timolol) have higher binding affinities for b receptors
than non-hetero aromatics due to additional interactions
with complementary sites on the receptor (Baker, 2005).
Each of the available b blockers has one or more chiral
centers in its structure, and in all cases, at least one of the
chiral carbon atoms residing in the alkyl side chain is
directly attached to a hydroxyl group (Fig. 1) (Baker,
2005). The enantiomers of beta-blockers possess markedly
different pharmacodynamics, and in some cases, pharma-
cokinetics. The available data regarding the pharmacologic
action of b blockers indicate that the interaction of these
agents with b adrenoceptors is highly stereoselective
(Pearson et al., 1989; Stoschitzky et al., 1993; Jeppsson
et al., 1984; Barrett and Cullum, 1968).
Generally, the cardiac beta-blocking activity of the b
blockers with two enantiomers resides in their (S)-enanti-
omers (Pearson et al., 1989; Stoschitzky et al., 1993;
Jeppsson et al., 1984; Barrett and Cullum, 1968), and the
reported S:R activity ratio being in the range of 33–530
(Horinouchi et al., 2009; Mehvar and Brocks, 2001;
Nathanson, 1988).
In the following of our research program toward
molecular modeling of compounds (Bekhradnia et al.,
2007, 2011, 2009; Arshadi et al., 2011; Kassaee et al.,
2008), we look at the molecular structure of some non-
selective beta-blockers. In this research, Propranolol,
123
Med Chem Res (2012) 21:2571–2578
Timolol, Nadolol, and Bunolol were studied as four rou-
tinely used non-selective beta-blockers.
activity.
Materials and methods
Rotational energy around the entire single bonds of 2, 3,
4, and 5 (Tables 1, 2, 3, 4), were determined using
ab initio HF calculation and STO-3G basis sets. Calcu-
lations were performed by means of the Gaussian 98
system of programs (GAUSSIAN, 1998). The geometrical
structures, corresponding to the ground states were
investigated at HF/STO-3G level of theory. To assess the
performance of this approach, all species were computed
at higher level. Consequently, the STO-3G outputs were
used as inputs for the HF/6-31G* calculations. The Har-
tree–Fock method usually works well for frequency pre-
dictions and geometry optimizations. Moreover, the
natural charges outcome Natural Bond Orbital analysis
(NBO) are calculated in ab initio method with 6-31G*
basis set. Structures, thermal energies (E), thermal
enthalpies (H), and thermal Gibbs free energies (G) for
each enantiomer are calculated at HF level of theory,
using 6-31G* basis sets. The ab initio calculation for each
enantiomer show higher stabilities for (S)-enantiomer
compared with (R)-antipode. A noticeable consistency is
found between results of HF theoretical calculations and
biological activity of these drugs.
Dihedral angles around the N2C3C4O5 bond confirm
that (S)- and (R)-Propranolol have the lowest and highest
dihedral angles related to other non-selective beta-block-
ers. Also, it is found the minimum variation for (S)- and
(R)-enantiomer around the N2C3C4O5 dihedral angle.
Therefore, propranolol is used clinically as racemic mix-
ture, whereas some of the others (e.g. bunolol and timo-
lol) are employed as pure (S)-enantiomer. It can be
related to differences of dihedral angles around the
N2C3C4O5 bond for (R)- and (S)-enantiomer in each drug.
In fact, some non-selective beta-blockers which are used
as racemic mixture, has a minimum difference around the
N2C3C4O5 dihedral angle for related (S)- and (R)-enanti-
omers. Apparently, the exceptions show the maximum
variation around mentioned dihedral angle. This is due to
interaction between active site of related stereoisomer and
beta-receptor. The reliable biological effects are found
when the beta-receptor and relative beta-adrenergic
antagonists’ active site are coordinated through the
N2C3C4O5 dihedral angle.
Additionally, the (S)-enantiomers of beta-blockers
reveal the more negative natural charges for oxygen atom
Med Chem Res (2012) 21:2571–2578 2573

Table 1 Energies (E), enthalpies (H), and Gibbs free energies (G) in (kcal mol-1), important bond angles (A), dihedral angles (D), bond length
(L), and natural charges for optimized Timolol enantiomers obtained by HF (6-31G*) calculations
R-Timolol
D(1,2,3,4) 153.621 Thermodynamic data (kcal mol-1) A(1,2,3) 118.824 L(1,2) 1.47072 Natural charges
D(2,3,4,5) 66.454 A(2,3,4) 109.295 L(2,3) 1.45519 1 0.150806
D(2,3,4,6) 169.169 Thermal energy -844155.163 A(3,4,5) 111.118 L(3,4) 1.52842 2 -0.741955
D(3,4,6,7) 168.873 A(3,4,6) 111.027 L(4,5) 1.40255 3 -0.145846
D(5,4,0.6,7) -69.427 Enthalpy -844243.751 A(5,4,6) 107.654 L(4,6) 1.51223 4 0.155443
D(6,7,8,9) 4.312 Free Gibbs energy -844155.297 A(4,6,7) 108.274 L(6,7) 1.441743 5 -0.754324
D(6,7,8,10) -175.203 A(6,7,8) 117.333 L(7,8) 1.32235 6 0.002964
A(7,8,10) 121.163 L(8,10) 1.47542 7 -0.676619
O A(7,8,9) 124.781 L(8,9) 1.26895 8 0.636416
9 -0.646797
10 0.524133
11 N
10 7 5 OH 11 -0.010638
O H
N 8
6 4 N 1
S N 3 2
9

Timolol

S-Timolol
D(1,2,3,4) 163.621 Thermodynamic data (kcal mol-1) A(1,2,3) 119.062 L(1,2) 1.47133 Natural charges
D(2,3,4,5) 286.983 Thermal energy -844159.210 A(2,3,4) 108.384 L(2,3) 1.45435 1 0.15543
D(2,3,4,6) -176.076 A(3,4,5) 110.289 L(3,4) 1.52831 2 -0.754565
D(3,4,6,7) -173.688 Enthalpy -844158.090 A(3,4,6) 111.393 L(4,5) 1.39622 3 -0.152973
D(5,4,0.6,7) 64.978 A(5,4,6) 108.117 L(4,6) 1.51315 4 0.158071
D(6,7,8,9) -6.484 Free Gibbs energy -844245.345 A(4,6,7) 107.354 L(6,7) 1.41476 5 -0.754324
D(6,7,8,10) 174.506 A(6,7,8) 117.941 L(7,8) 1.32098 6 0.002964
A(7,8,10) 120.557 L(8,10) 1.47346 7 -0.676619
O A(7,8,9) 125.218 L(8,9) 1.26844 8 0.636416
9 -0.646797
10 0.524133
11 N
10 7 5 OH 11 -0.010638
O H
N 8
6 4 N 1
S N 3 2
9

Timolol

in hydroxyl as well as nitrogen atom in aryloxypropanol-
amine group than related antipode.
To attain a deeper insight, the crystal of propranolol in
racemic form can be compared with our theoretical study.
The comparing parameters are given in Table 5.
Results and discussion
Computational chemistry has proved really useful for the
accurate interpretation of the structural and kinetic infor-
mation available for a wide variety of stereoisomers and
behavior of biological effects. In this article, ab initio
method with 6-31G* basis set was employed for investi-
gating the geometrical optimization and pharmaceutical
classification of Timolol, Nadolol, Bunolol, and Propran-
olol enantiomers (Fig. 2). These were along with the cal-
culated energy separating the low energy stereoisomer for
each drug.
In order to determine the lower energy for each enan-
tiomer, we calculated the electronic energies of the mole-
cules as a function of the chiral carbon in the identical
propanol side chain. The final optimized geometric struc-
tural parameters of enantiomers of these beta-blockers

123
2574 Med Chem Res (2012) 21:2571–2578

Table 2 Energies (E), enthalpies (H), and Gibbs free energies (G) in (kcal mol-1), important bond angles (A), dihedral angles (D), bond length
(L), and natural charges for optimized Nadolol enantiomers obtained by HF (6-31G*) calculations
R-Nadolol
D(1,2,3,4) 160.297 Thermodynamic data (kcal mol-1) A(1,2,3) 118.798 L(1,2) 1.46953 Natural charges
D(2,3,4,5) 67.838 Thermal energy -635307.222 A(2,3,4) 109.323 L(2,3) 1.45255 1 0.163099
D(2,3,4,6) 170.553 A(3,4,5) 110.799 L(3,4) 1.52809 2 -0.743395
D(3,4,6,7) 166.597 Enthalpy -635306.103 A(3,4,6) 111.358 L(4,5) 1.40513 3 -0.130636
D(5,4,0.6,7) -71.8035 A(5,4,6) 107.592 L(4,6) 1.51509 4 -0.756551
D(6,7,8,9) 2.36261 Free Gibbs energy -635395.517 A(4,6,7) 108.196 L(6,7) 1.40051 5 -0.75879
D(6,7,8,10) -177.677 A(6,7,8) 120.431 L(7,8) 1.35052 6 0.156124
A(7,8,10) 115.085 L(8,10) 1.40445 7 0.011467
A(7,8,9) 123.879 L(8,9) 1.38059 8 -0.291693
H
OH 9 -0.184692
H
10 0.440444
HO 11 11 -0.314869
10 7 5 OH
O H
8 4 N 1
6
3 2
9

Nadolol

S-Nadolol
D(1,2,3,4) 164.12 Thermodynamic data (kcal mol-1) A(1,2,3) 119.142 L(1,2) 1.47081 Natural charges
D(2,3,4,5) 286.677 Thermal energy -635308.455 A(2,3,4) 108.519 L(2,3) 1.45432 1 0.15662
D(2,3,4,6) -176.563 A(3,4,5) 110.171 L(3,4) 1.52849 2 -0.751789
D(3,4,6,7) -168.939 Enthalpy -635307.335 A(3,4,6) 11.504 L(4,5) 1.39502 3 -0.152664
D(5,4,0.6,7) 69.707 A(5,4,6) 108.266 L(4,6) 1.51565 4 0.167872
D(6,7,8,9) -7.285 Free Gibbs energy -635396.008 A(4,6,7) 108.114 L(6,7) 1.39898 5 -0.765755
D(6,7,8,10) 173.573 A(6,7,8) 120.463 L(7,8) 1.35952 6 0.003756
A(7,8,10) 115.144 L(8,10) 1.40453 7 -0.69511
H A(7,8,9) 123.846 L(8,9) 1.38147 8 0.433268
H OH 9 -0.27649
HO 11
10 -0.07229
7 5 OH 11 -0.318952
10
O H
8 4 N 1
6
3 2
9

Nadolol

were obtained by HF/6-31G* calculations (Tables 1, 2, 3,
4). Attention is particularly paid to the stereoisomerism of
above beta-blockers around the hydroxyl-bearing carbon of
the aryloxypropanolamine. This rather detailed theoretical
study is accounted for under the following objects: geom-
etries, thermodynamics, and natural charges outcome of
NBO for stereoisomers.
Complete geometry optimizations are performed on the
method of HF/6-31G*. The major structural features of
these molecules are briefly summarized in Tables 1, 2, 3,
and 4. Docking the S isomer of beta-blockers into the
beta2-adrenergic binding site have shown the isopropyl
side chains is the key where the amine and hydroxyl groups
are interacting with Asp113 and Asn293 (Topiol and Sabio,

123
Med Chem Res (2012) 21:2571–2578 2575

Table 3 Energies (E), enthalpies (H), and Gibbs free energies (G) in (kcal mol-1), important bond angles (A), dihedral angles (D), bond length
(L), and natural charges for optimized Bunolol enantiomers obtained by HF (6-31G*) calculations
R-Bunolol
D(1,2,3,4) 159.499 Thermodynamic data (kcal mol-1) A(1,2,3) 118.812 L(1,2) 1.47432 Natural charges
D(2,3,4,5) 67.571 Thermal energy -563207.322 A(2,3,4) 109.323 L(2,3) 1.45444 1 0.03479
D(2,3,4,6) 170.370 A(3,4,5) 110.832 L(3,4) 1.53212 2 -0.734985
D(3,4,6,7) 167.322 Enthalpy -563206.221 A(3,4,6) 111.412 L(4,5) 1.40123 3 -0.13958
D(5,4,0.6,7) -70.962 A(5,4,6) 107.598 L(4,6) 1.51112 4 0.15015
D(6,7,8,9) 8.968 Free Gibbs energy -563287.369 A(4,6,7) 108.198 L(6,7) 1.3898 5 0.186936
D(6,7,8,10) -171.826 A(6,7,8) 120.689 L(7,8) 1.3454 6 -0.00179
A(7,8,10) 116.488 L(8,10) 1.40123 7 -0.69602
A(7,8,9) 122.898 L(8,9) 1.3798 8 -0.56397
11 9 0.41855
7 5 OH 10 -0.39952
10
O O 11 -0.30933
H
8 4 N 1
6
9 3 2

Bunolol

S-Bunolol
D(1,2,3,4) 168.132 Thermodynamic data (kcal mol-1) A(1,2,3) 116.099 L(1,2) 1.46123 Natural charges
D(2,3,4,5) 286.298 Thermal energy -563198.212 A(2,3,4) 108.898 L(2,3) 1.45211 1 0.03840
D(2,3,4,6) -176.896 A(3,4,5) 110.097 L(3,4) 1.52221 2 -0.750913
D(3,4,6,7) -170.618 Enthalpy -563197.099 A(3,4,6) 111.556 L(4,5) 1.37431 3 -0.15260
D(5,4,0.6,7) 68.059 A(5,4,6) 108.187 L(4,6) 1.5099 4 0.16330
D(6,7,8,9) -15.343 Free Gibbs energy -563280.088 A(4,6,7) 107.897 L(6,7) 1.40123 5 -0.765532
D(6,7,8,10) 165.457 A(6,7,8) 120.368 L(7,8) 1.3486 6 0.00121
A(7,8,10) 115.587 L(8,10) 1.40123 7 -0.69453
A(7,8,9) 123.869 L(8,9) 1.3798 8 0.41702
11 9 -0.25356
7 5 OH 10 -0.05037
10
O O 11 -0.31608
H
8 4 N 1
6
9 3 2

Bunolol

2008). In each case, the amino-propyl-hydroxyl segments
overlap well. These indicate that N2C3C4O5 is the most
important fragment in biological activity of these drugs.
The small degrees of non-planarity for these drugs are
measured through their dihedral angles N2C3C4O5. Dihe-
dral angles around the N2C3C4O5 bond are calculated for
each stereoisomer. These were found for (S, R)-enantio-
mers of Timolol, Nadolol, Bunolol, and Propranolol which
are as follows: (286.983, 66.454); (286.677, 67.838);
(286.298, 67.571), and (285.076, 78.586), respectively
(Tables 1, 2, 3, 4). Correspondingly, among the studied
drugs, (S)- and (R)-Propranolol have the lowest and highest
dihedral angles around the N2C3C4O5 bond.
After carrying out geometry optimization calculations at
the HF level and determining the thermal energies (E),
thermal enthalpies (H), and thermal Gibbs free energies
(G) for each enantiomer of considered drugs, the results
were tabulated in Tables 1, 2, 3, and 4. These portray that
(S)-enantiomers are more stable than related (R)-enantio-
mer. Also, (S)-enantiomers are important for energetic

123
2576 Med Chem Res (2012) 21:2571–2578

Table 4 Energies (E), enthalpies (H), and Gibbs free energies (G) in (kcal mol-1), important bond angles (A), dihedral angles (D), bond length
(L), and natural charges for optimized Propranolol enantiomers obtained by HF (6-31G*) calculations
R-Propranolol
D(1,2,3,4) -170.122 Thermodynamic data (kcal mol-1) A(1,2,3) 115.879 L(1,2) 1.4498 Natural charges
D(2,3,4,5) 78.586 Thermal energy -515524.111 A(2,3,4) 109.219 L(2,3) 1.4498 1 0.0349761
D(2,3,4,6) -173.958 A(3,4,5) 111.057 L(3,4) 1.5196 2 -0.724099
D(3,4,6,7) -64.814 Enthalpy -515522.102 A(3,4,6) 113.365 L(4,5) 1.40123 3 -0.120652
D(5,4,0.6,7) 60.459 A(5,4,6) 110.188 L(4,6) 1.5169 4 0.131253
D(6,7,8,9) -0.105 Free Gibbs energy -515600.452 A(4,6,7) 107.598 L(6,7) 1.49124 5 -0.762059
D(6,7,8,10) -179.997 A(6,7,8) 120.288 L(7,8) 1.35432 6 -0.03340
A(7,8,10) 115.018 L(8,10) 1.43432 7 -0.723861
A(7,8,9) 124.216 L(8,9) 1.3597 8 0.466922
11 9 -0.293322

10 7 5 OH 10 -0.097253
O 11 -0.166702
H
8 4 N 1
6
3 2
9

Propanolol

S-Propranolol
D(1,2,3,4) 168.568 Thermodynamic data (kcal mol-1) A(1,2,3) 115.973 L(1,2) 1.46302 Natural charges
D(2,3,4,5) 285.076 Thermal energy -515525.269 A(2,3,4) 108.746 L(2,3) 1.45652 1 0.040415
D(2,3,4,6) -175.652 A(3,4,5) 110.196 L(3,4) 1.52517 2 -0.754984
D(3,4,6,7) -65.301 Enthalpy -515524.149 A(3,4,6) 113.237 L(4,5) 1.39868 3 -0.149132
D(5,4,0.6,7) 173.771 A(5,4,6) 106.003 L(4,6) 1.5178 4 0.166931
D(6,7,8,9) -0.742 Free Gibbs energy -515601.813 A(4,6,7) 108.02 L(6,7) 1.40407 5 -0.782603
D(6,7,8,10) 179.352 A(6,7,8) 120.089 L(7,8) 1.34794 6 -0.017278
A(7,8,10) 115.017 L(8,10) 1.43238 7 -0.710772
A(7,8,9) 124.519 L(8,9) 1.36137 8 0.467674
11 9 -0.2971452
7 5 OH 10 -0.1042182
10
O H 11 -0.1927931
8 4 N 1
6
3 2
9

Propanolol

description of each drug. All of these drugs possess
intrinsic high degree of enantioselectivity in binding to the
beta-adrenergic receptor. The (S)-enantiomer organize
much greater affinity for the binding to the beta-adrenergic
receptors than corresponding (R)-enantiomer.
Natural charges were calculated for each atom in men-
tioned molecules at the HF level with 6-31G* basis set
(Tables 1, 2, 3, 4). However, aryloxypropanolamine group
includes the most important atom in these molecules.
Whereas, this functional group is the active site in all
enantiomers, and organizes the biological activity of non-
selective beta-blockers. Nitrogen and oxygen atoms in above
functional group act especially as active sites and can bind to
beta-receptor. Natural charges for oxygen atom of hydroxyl
and nitrogen atom for (S)-timolol are -0.754324 and
-0.754565 as well as in (R)-timolol are -0.754324 and
-0.741955, respectively. These cases are found for
(S)- and (R)-Nadolol as follows: (-0.765755, -0.751789)
and (-0.75879, -0.743395), respectively. Also, above
natural charges are calculated for (S)- and (R)-Bunolol

123
Med Chem Res (2012) 21:2571–2578 2577

Table 5 Some of the bond angles (A, angstrom) and bond lengths Furthermore, all conformers in crystal structure are found
(L, degree) for crystal of propranolol and optimized calculated in thermal equilibrium and racemic forms, whereas our
propranolol
calculations are performed for chiral molecules.
Parameters Obtained by theoretical Obtained by
calculation X-ray data Acknowledgments This research was partially supported by a grant
from Pharmaceutical Research Network, Tehran, Iran and Pharma-
A(3,4,5) 110.2 109.6 ceutical Sciences Research Center of Mazandaran University of
A(2,3,4) 108.7 112.2 Medical Sciences, Sari, Iran. The authors gratefully acknowledge the
A(1,2,3) 115.9 112.5 financial support of this study by the Mazandaran University of
Medical Sciences ‘‘Professor’s projects funds’’ and ‘‘Pharmaceutical
A(5,4,6) 106 107.4 Research Network of Iran’’.
A(4,6,7) 108 103.4
A(3,4,6) 113.2 110.7
L(7,8) 1.347 1.386
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L(6,7) 1.404 1.446
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