Zhang X, De Los Angeles J E, He M Y, Dalton J T, Shams G, Lei L, Patil P N, Feller D R, Miller D D, Hsu F L
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis 38163, USA.
J Med Chem. 1997 Sep 12;40(19):3014-24. doi: 10.1021/jm960642q.
The synthesis and the biological evaluation of a new series of medetomidine analogs are reported. The substitution pattern at the phenyl ring of the tetralin analogs had a distinct influence on the alpha 2-adrenoceptor binding affinity. 4-Methylindan analog 6 was the most potent alpha 2-adrenoceptor binding ligand among these 4-substituted imidazoles, and its alpha 2-adrenoceptor selectivity was greater than the 5-methyl tetralin analog 4c. Ligand-pharmacophore and receptor modeling were combined to rationalize alpha 2-adrenoceptor binding data of the imidazole analogs in terms of ligand-receptor interactions. The structure-activity relationships that were apparent from this and previous studies were qualitatively rationalized by the binding site models of the alpha 2-adrenoceptor. The benzylic methyl group of medetomidine or the naphthyl analog 2a was superimposable with the alpha-methyl group of (-)-alpha-methylnorepinephrine and fit into the proposed "methyl pocket" of the alpha 2-adrenoceptor defined by the residues Leu110, Leu169, Phe391, and Thr395.
报道了一系列新型美托咪定类似物的合成及生物学评价。四氢萘类似物苯环上的取代模式对α2-肾上腺素能受体结合亲和力有显著影响。在这些4-取代咪唑中，4-甲基茚类似物6是最有效的α2-肾上腺素能受体结合配体，其α2-肾上腺素能受体选择性大于5-甲基四氢萘类似物4c。结合配体药效团和受体模型，从配体-受体相互作用的角度对咪唑类似物的α2-肾上腺素能受体结合数据进行了合理化分析。从本研究及先前研究中明显看出的构效关系，通过α2-肾上腺素能受体的结合位点模型进行了定性合理化。美托咪定或萘类似物2a的苄基甲基与(-)-α-甲基去甲肾上腺素的α-甲基重叠，并适合由Leu110、Leu169、Phe391和Thr395残基定义的α2-肾上腺素能受体的拟“甲基口袋”。
