SYNTHESIS AND EVALUATION OF 6,11-ETHANOHEXAHYDROBENZO[B]QUINOLIZIDINES - A NEW CLASS OF NONCOMPETITIVE N-METHYL-D-ASPARTATE ANTAGONISTS

The synthesis and in vitro and in vivo evaluation of 2,13-cycloalkyl-6 ,11-ethanobenzo[b]quinolizidines, a new class of noncompetitive N-meth yl-D-aspartate (NMDA) antagonists acting at the PCP site on the NMDA r eceptor complex, is reported. Structure-activity relationship studies led to the identification of 10-hydroxy-(6 alpha,11 alpha,11 alpha ',2 ']-endo-cyclopenta-2H-pyrido[1,2-b]isoquinoline hydrobromide (5h) and 9-hydroxy-(6 alpha,11 alpha,11 alpha ',2']-endo-cyclopenta-2H-pyrido[1 ,2-b]isoquinoline hydrobromide(5i), the most potent members of this se ries with K-i values of 2.3 +/- 0.2 and 2.3 +/- 0.5 nM, respectively. Molecular modeling studies revealed that this series of compounds occu pies both lipophilic sites of the Andrews PCP receptor model and share s structural features which are common to other classes of known nonco mpetitive NMDA antagonists such as MK-801.