Subramanyam C, Mallamo J P, Pilling G M, Earley W G, Carabateas P M, Wetzel J R, DeHaven-Hudkins D, Allen T, Kullnig R K
Department of Medicinal Chemistry, Sanofi Winthrop Inc., Collegeville, Pennsylvania 19426, USA.
J Med Chem. 1995 Jun 23;38(13):2483-9. doi: 10.1021/jm00013a025.
The synthesis and in vitro and in vivo evaluation of 12,13-cycloalkyl-6,11-ethanobenzo[b]-quinolizidines, a new class of noncompetitive N-methyl-D-aspartate (NMDA) antagonists acting at the PCP site on the NMDA receptor complex, is reported. Structure-activity relationship studies led to the identification of 10-hydroxy-(6 alpha,11 alpha,11 alpha beta,12R*,13S*)-1,3,4,6,11,11a,13,14,15,16-decahydro-12H- 6,11[1',2']-endo-cyclopenta-2H-pyrido[1,2-b]isoquinoline hydrobromide (5h) and 9-hydroxy-(6 alpha,11 alpha,11a beta,12R*,13S*)- 1,3,4,6,11,11a,13,14,15,16-decahydro-12H-6,11-[1',2']-endo-cycl ope nta-2H- pyrido[1,2-b]isoquinoline hydrobromide (5i), the most potent members of this series with Ki values of 2.3 +/- 0.2 and 2.3 +/- 0.5 nM, respectively. Molecular modeling studies revealed that this series of compounds occupies both lipophilic sites of the Andrews PCP receptor model and shares structural features which are common to other classes of known noncompetitive NMDA antagonists such as MK-801.
报道了一类新型非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂——12,13-环烷基-6,11-亚乙基苯并[b]喹嗪啶的合成及其体外和体内评价。该类拮抗剂作用于NMDA受体复合物上的苯环己哌啶（PCP）位点。构效关系研究确定了10-羟基-（6α,11α,11αβ,12R*,13S*）-1,3,4,6,11,11a,13,14,15,16-十氢-12H-6,11[1',2']-内-环戊二烯并-2H-吡啶并[1,2-b]异喹啉氢溴酸盐（5h）和9-羟基-（6α,11α,11aβ,12R*,13S*）-1,3,4,6,11,11a,13,14,15,16-十氢-12H-6,11-[1',2']-内-环戊二烯并-2H-吡啶并[1,2-b]异喹啉氢溴酸盐（5i），它们是该系列中活性最强的成员，其抑制常数（Ki）值分别为2.3±0.2和2.3±0.5 nM。分子模拟研究表明，该系列化合物占据了安德鲁斯PCP受体模型的两个亲脂性位点，并具有与其他已知非竞争性NMDA拮抗剂（如MK-801）共有的结构特征。
