Mellin C, Vallgårda J, Nelson D L, Björk L, Yu H, Andén N E, Csöregh I, Arvidsson L E, Hacksell U
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Sweden.
J Med Chem. 1991 Feb;34(2):497-510. doi: 10.1021/jm00106a004.
The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.
顺式和反式-1,2,3,4,4a,5,10,10a-八氢-9-羟基-1-丙基苯并[g]喹啉（分别为10和11）的对映体以及反式-1,2,3,4,4a,5,6,10b-八氢-10-羟基-4-丙基苯并[f]喹啉（12）的对映体已被合成，并且通过X射线晶体学和分子力学（MMP2）计算研究了它们的立体化学和构象特征。这些化合物是强效5-羟色胺（5-HT）受体激动剂8-羟基-2-（二丙基氨基）四氢萘（8-OH-DPAT；1）的构象受限类似物，已通过大鼠的生化和行为测试评估了其对中枢5-HT和多巴胺受体的刺激活性。此外，我们还评估了这些化合物以及一些先前报道的类似物从5-HT1A结合位点置换[3H]-8-OH-DPAT的能力。12的对映体表现为强效5-HT1A受体激动剂，而八氢苯并[g]喹啉衍生物的效力则低得多或无活性。一般来说，这些化合物的亲和力与其激动剂效力密切相关。所研究的这组化合物由一种新型的基于计算机图形学的5-HT1A受体激动模型所涵盖。该模型由一个灵活的药效团和一个部分受体排除体积组成。
