title: Differentiation of alpha-adrenergic receptors using pharmacological evaluation and molecular modeling of selective adrenergic agents.
abstract: Subtypes of alpha adrenergic receptors were studied using selective adrenergic agonists. A-53693, A-54741, and related compounds were evaluated for their affinity for alpha receptor subtypes using radioligand binding techniques. Efficacy and potency were also evaluated using in vitro bioassays of alpha-1 receptors in rabbit aorta smooth muscle and alpha-2 receptors in the phenoxybenzamine-pretreated canine saphenous vein. Active and inactive compounds were then submitted for computer-assisted molecular modeling evaluation to ascertain the structural requirements for optimal potency and selectivity. Rigid catecholamines such as A-53693 display a high degree of selectivity for alpha-2 compared to alpha-1 receptors, probably because of the unique regions of space at the ligand binding site occupied by active compounds. Imidazolines such as A-54741 also interact with extremely high affinity and potency for alpha-2 receptors, and to a lesser extent at alpha-1 receptors. The spatial domains occupied by phenethylamines and imidazolines differ, each having unique regions of permissable space at alpha receptors. Compounds such as A-53693 and A-54741 are extremely useful probes of the molecular interactions of alpha agonistic compounds which will help in the design of even more selective drugs for alpha adrenergic receptors.
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D054833:Isoindoles; D008958:Models, Molecular; D009281:Naphthalenes / Q000494:pharmacology*; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000145:classification* / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D009281:Naphthalenes; D011942:Receptors, Adrenergic, alpha; D013764:Tetrahydronaphthalenes; C056298:5,6-dihydroxy-1-(2-imidazolinyl)tetralin; C056299:A 53693