Hancock A A, Kyncl J J, Martin Y C, DeBernardis J F
Abbott Laboratories, Abbott Park, IL 60064.
J Recept Res. 1988;8(1-4):23-46. doi: 10.3109/10799898809048976.
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.
使用选择性肾上腺素能激动剂研究了α肾上腺素能受体的亚型。利用放射性配体结合技术评估了A-53693、A-54741及相关化合物对α受体亚型的亲和力。还通过兔主动脉平滑肌中α-1受体和经酚苄明预处理的犬隐静脉中α-2受体的体外生物测定来评估效力和效能。然后将活性和非活性化合物提交进行计算机辅助分子建模评估，以确定最佳效力和选择性的结构要求。与α-1受体相比，刚性儿茶酚胺如A-53693对α-2受体表现出高度的选择性，这可能是由于活性化合物在配体结合位点占据的独特空间区域所致。咪唑啉类如A-54741也以极高的亲和力和效力与α-2受体相互作用，而与α-1受体的相互作用程度较小。苯乙胺类和咪唑啉类占据的空间结构域不同，每种在α受体处都有允许空间的独特区域。诸如A-53693和A-54741之类的化合物是α激动剂化合物分子相互作用的极其有用的探针，这将有助于设计出对α肾上腺素能受体更具选择性的药物。
