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Adrenergic Receptors
Adrenergic Receptors
Adrenergic Receptors
The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamine, especially nor adrenaline (nor epinephrine) and adrenaline (epinephrine). Although dopamine is a catecholamine, its receptors are in a different category. Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic response (e.g. the fight-or-flight response). For instance, the heart rate will increase and the pupils will dilate, energy will be mobilized, and blood flow diverted from other nonessential organs to skeletal muscle. BASIC STRUCTURES:PHENYLETHANOLAMINE:-
PHENYLETHYLAMINE:-
RECEPTORS
AGONISTS
ANTAGONISTS.
1: A, B, D
(Alpha-1 blockers) (TCA:s) Amitriptyline Clomipramine Doxepin Trimipramine Phentolamine Prazosin Tamsulosin Terazosin
Alpha-2 blockers) 2: A, B, C Epinephrine Smooth muscle norepinephrine relaxation and >> isoprenaline neurotransmitter inhibition (Alpha-2 agonists)
Metoprolol Atenolol
(Beta blockers)
Salbutamol (Albuterol in USA) Bitolterol mesylate Formoterol Isoprenaline Levalbuterol Metaproterenol Salmeterol Terbutaline Ritodrine
Butoxamine Propranolol
Amibegron Solabegron
SR 59230A
NOR-ADRENALINE
PHENYLEPHRINE.
METHOXAMINE.
PHENTOLAMINE.
PRAZOSIN.
AMITRIPTYLINE
CLONIDINE
AMITRAZ
ATIPAMEZOLE.
IDAZOXAN
DOBUTAMINE
ISOPRENALINE
ATENOLOL.
SALBUTAMOL
TERBUTALINE
PROPANOLOL
SOLABEGRON
SR- 59230A
STRUCTURE ACTIVITY RELATION OF PHENYLETHYLAMINE DERIVATIVES:The group of phenethylamine derivatives is referred to as the phenethylamine. Substituted phenethylamine, substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx) are a series of broad and diverse classes of compounds derived from phenethylamine that include stimulants, psychedelics, and entactogens, as well as anorectics, bronchodilators, decongestants, and antidepressants, among others. a phenethylamine core with a methyl group attached to the alpha carbon resulting in amphetamine, along with additional substitutions. Examples of amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone amphetamine and methamphetamine which lack both ring substituents and a side chain hydroxyl, are sufficiently lipophilic to cross the blood brain barrier readily and cause dramatic CNS stimulation. Ephedrine is a substituted amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl (OH). Ephedrine is a sympathomimetic amine. The principal mechanism of its action relies on its indirect stimulation of the adrenergic receptor system, which is part of the sympathetic nervous system (SNS), by increasing the neither activity of nor adrenaline at the post-synaptic and -receptors. The presence of direct interactions with -receptors is unlikely, but still controversial. Action upon the central nervous system (CNS) is limited because ephedrine only crosses the blood-brain barrier weakly and not very efficiently.
The presence of an N-methyl group decreases binding affinities at -receptors, compared with nor ephedrine. On the other hand ephedrine binds better than N-methyl ephedrine, which has an additional methyl group at the N-atom. Also the steric orientation of the hydroxyl group is important for receptor binding and functional activity
Both ephedrine and pseudoephedrine act as a bronchodilator
AMPHETAMINE
EPHEDRINE
METHAMPHETAMINE
STRUCTURE ACTIVITY RELATION OF PHENYLETHANOLAMINE DERIVATIVES:1. Primary or Secondary Amine, charged at physiological pH 2. Hydroxyl at Beta carbon in the R configuration for maximum effect 3. R1, R2, R3 control selectivity and Metabolism
BASIC STRUCTURE
R1 substitutions
R2 substitutions
Methyl slow
Ethyl block
R1 - larger than a methyl R1 - Larger than isopropyl generally target Beta-2 Adrenergic Receptors R2 - Methyl or larger R3
o o o
If only one hydroxyl, must be 4' If two hydroxyls, many combination of 3,4,5 are possible Can be as large a formyl, but must be able to hydrogen bond
R1 Guanidine Alpha
o
and Imidazoline
R1 - Methyl or smaller R2 - S (-) Enantiomer R2 - must be no larger than methyl R3 - Lone hydroxyl at 3' is selective for Alpha-1 Adrenergic Receptors (Phenylephrine) R3 - 2,5 dimethoxy alpha selective
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