Mellin C, Björk L, Karlén A, Johansson A M, Sundell S, Kenne L, Nelson D L, Andén N E, Hacksell U
Department of Organic Pharmaceutical Chemistry, University of Uppsala, Sweden.
J Med Chem. 1988 Jun;31(6):1130-40. doi: 10.1021/jm00401a012.
A number of stereochemically well defined C3-methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been synthesized, and their stereochemical characteristics have been studies by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations. The compounds were tested for activity at central 5-HT and dopamine (DA) receptors, by use of biochemical and behavioral tests in rats. In addition, the ability of the cis- and trans-8-hydroxy-3-methyl-2-(di-n-propylamino)tetralins (15 and 11) to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The stereoselectivity of the interaction of 11 and 15 with 5-HT receptors was much greater than that of 8-OH-DPAT. Observed rank order of potencies in the 5-HT1A binding assay corresponds to that in the in vivo biochemical assay.
已合成了多种立体化学结构明确的强效5-羟色胺（5-HT）受体激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）的C3-甲基化衍生物，并通过核磁共振光谱、X射线晶体学和分子力学计算研究了它们的立体化学特征。利用大鼠的生化和行为测试，对这些化合物在中枢5-HT和多巴胺（DA）受体上的活性进行了测试。此外，还评估了顺式和反式8-羟基-3-甲基-2-（二正丙基氨基）四氢萘（15和11）从5-HT1A结合位点置换[3H]-8-OH-DPAT的能力。11和15与5-HT受体相互作用的立体选择性远大于8-OH-DPAT。在5-HT1A结合试验中观察到的效价顺序与体内生化试验中的顺序一致。
