Huff J R, Baldwin J J, deSolms S J, Guare J P, Hunt C A, Randall W C, Sanders W S, Smith S J, Vacca J P, Zrada M M
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
J Med Chem. 1988 Mar;31(3):641-5. doi: 10.1021/jm00398a025.
Hexahydroaryl[a]quinolizines comprise a prominent structural element in several alpha 2-adrenoceptor antagonists. Eight hexahydroheteroarylquinolizines were prepared as minimal ligands to investigate the relationship between the nature of the aromatic ring and affinity of these molecules for alpha-adrenoceptors. Affinity for alpha 1-and alpha 2-adrenoceptors was assessed by displacement of [3H]prasozin and [3H]clonidine, respectively. Lipophilicity of the aryl portion of the molecules, reflected by their partition coefficient between octanol and pH 7.4 buffer, correlated well with affinity at both receptor subtypes. Although some compounds showed nanomolar affinity for alpha-adrenoceptors, no subtype selectivity was observed. These results suggest that the aromatic ring enhances binding at both receptors chiefly through hydrophobic interactions and contributes little to subtype selectivity.
六氢芳基[a]喹嗪是几种α2-肾上腺素能受体拮抗剂中的一个重要结构单元。制备了八个六氢杂芳基喹嗪作为最小配体，以研究芳环的性质与这些分子对α-肾上腺素能受体亲和力之间的关系。分别通过[3H]哌唑嗪和[3H]可乐定的置换来评估对α1-和α2-肾上腺素能受体的亲和力。分子芳基部分的亲脂性，由其在辛醇和pH 7.4缓冲液之间的分配系数反映，与两种受体亚型的亲和力都有很好的相关性。尽管一些化合物对α-肾上腺素能受体显示出纳摩尔级别的亲和力，但未观察到亚型选择性。这些结果表明，芳环主要通过疏水相互作用增强在两种受体上的结合，对亚型选择性贡献很小。
