Meyer M D, DeBernardis J F, Hancock A A
Abbott Laboratories, Abbott Park, Illinois 60064.
J Med Chem. 1994 Jan 7;37(1):105-12. doi: 10.1021/jm00027a013.
A series of cis- and trans-fused hexahydroindeno[2,1-c]pyridines have been prepared and evaluated for affinity and selectivity at the 5-HT1A subtype of the serotonin receptor. Using molecular modeling studies we predicted that the 5-methoxy-trans-fused members of this class would exhibit affinity for this site. In agreement with these predictions, trans-5-methoxy-N-propyl-2,3,4,4a,9,-9a-hexahydro-1H-indeno[2,1-c]pyridi ne (6a) demonstrated moderate affinity and high selectivity for the 5-HT1A binding site, whereas the cis-fused isomer 5a demonstrated virtually no affinity at this site. Additional trans-fused analogs from this series, where the nitrogen was substituted with a variety of alkylene imide containing appendages, demonstrated high (0.60-51 nM) affinity and excellent selectivity for the 5-HT1A site. Certain of these analogs, independent of ring-fusion stereochemistry, also demonstrated high affinity for the 5-HT2 binding site.
已制备了一系列顺式和反式稠合的六氢茚并[2,1-c]吡啶，并对其在血清素受体5-HT1A亚型上的亲和力和选择性进行了评估。通过分子模型研究，我们预测该类别的5-甲氧基-反式稠合成员对该位点具有亲和力。与这些预测一致，反式-5-甲氧基-N-丙基-2,3,4,4a,9,9a-六氢-1H-茚并[2,1-c]吡啶（6a）对5-HT1A结合位点表现出中等亲和力和高选择性，而顺式稠合异构体5a在该位点几乎没有亲和力。该系列中的其他反式稠合类似物，其中氮被各种含亚烷基酰亚胺的附属基团取代，对5-HT1A位点表现出高（0.60 - 51 nM）亲和力和优异的选择性。这些类似物中的某些，与环稠合立体化学无关，对5-HT2结合位点也表现出高亲和力。
