Synthesis and Evaluation of 6,11-Ethanohexahydrobenzoquinolizidines: A New Class of Noncompetitive N-Methyl -D-aspartate Antagonists

Article abstract of DOI:10.1021/jm00013a025

The synthesis and in vitro and in vivo evaluation of 12,13-cycloalkyl-6,11-ethanobenzoquinolizidines, 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-(6α,11α,11aβ,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-(6α,11α,11aβ,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 (5i), the most potent members of this series 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 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.