Zhang X, Yao X T, Dalton J T, Shams G, Lei L, Patil P N, Feller D R, Hsu F L, George C, Miller D D
Division of Medicinal Chemistry & Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210, USA.
J Med Chem. 1996 Jul 19;39(15):3001-13. doi: 10.1021/jm9506074.
A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.
已制备了一系列新的美托咪定萘类似物，并对其α-肾上腺素能活性进行了评估。甲基萘基类似物5a对α2-肾上腺素能受体表现出显著的选择性，在大鼠主动脉制剂中表现为部分α1-激动剂。相比之下，Z-乙烯基类似物8c具有α1-选择性，表现为强效α1-拮抗剂。两种刚性类似物（6和7）在α1-与α2-受体的结合亲和力上表现出很大差异，这表明5a的构象灵活性对于实现α-肾上腺素能活性很重要。分子模拟研究始于对经典苯乙胺和美托咪定类似物的构象分析。将美托咪定的构象与苯乙胺的构象叠加，为新咪唑类化合物的α2-肾上腺素能活性提供了一个初步解释。提出了苯乙胺和咪唑与α2-肾上腺素能受体的共同结合模式。对4-取代咪唑生物特性的了解，结合计算机辅助分子模拟得出的信息，为这类新型肾上腺素能药物的结构和构象要求提供了新的见解。
