Hong S S, Romstedt K J, Feller D R, Hsu F L, Cupps T L, Lyon R A, Miller D D
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210-1291.
J Med Chem. 1994 Jul 22;37(15):2328-33. doi: 10.1021/jm00041a011.
The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.
美托咪定的萘类似物（1），4-[1-(1-萘基)乙基]-1H-咪唑（2），是一种高效、选择性的α2-肾上腺素能受体激动剂。我们已开展一项构效关系研究，用氢、羟基、甲氧基、羰基或三氟甲基取代2中萘环与咪唑环之间碳桥上的甲基，并将它们的生物活性与美托咪定1以及2的光学异构体进行比较。2的类似物是α2A-肾上腺素能受体介导的人血小板聚集的拮抗剂，也是豚鼠回肠中α1-和α2-肾上腺素能受体的激动剂。这些类似物在血小板（α2A亚型）和豚鼠回肠（α1亚型）上的活性顺序和效力几乎相同，而外消旋体和S-(+)-2、去甲基和羟基类似物是豚鼠回肠中α2-肾上腺素能受体的强效激动剂。除去甲基类似物5外，其他类似物在α2A-（人血小板）、α1-（豚鼠回肠）或α2-（豚鼠回肠）肾上腺素能受体系统上均不如母体药物2有效。与类似物2一样，去甲基和甲氧基取代的类似物在功能（激动剂活性）和生化（受体置换）研究中均保持较高的α2/α1选择性。受体结合研究表明，在大鼠脑内，S-(+)-2在α1-和α2-肾上腺素能受体上的亲和力均高于R-(-)-异构体。此外，R-(-)-2在豚鼠回肠的α2-肾上腺素能受体中未表现出激动剂活性，作为人血小板中α2A-肾上腺素能受体的拮抗剂，其效力比S-(+)-2强10倍。因此，萘环与咪唑环之间碳桥上取代基的性质和手性在维持4-取代咪唑类化合物强效的α2-肾上腺素能受体活性和高α2/α1选择性方面起着重要作用。
