Synthesis and Evaluation of 6,11-Ethanohexahydrobenzo[b]quinolizidines: A New Class of Noncompetitive N-Methyl-D-aspartate Antagonists

Autor:	Chakrapani Subramanyam, William G. Earley, Joseph R. Wetzel, John P. Mallamo, Diane L. DeHaven-Hudkins, Gary M. Pilling, Philip M. Carabateas, Timothy Allen, Rudolph K. Kullnig
Rok vydání:	1995
Předmět:	Male Magnetic Resonance Spectroscopy Molecular model Chemistry Stereochemistry Antagonist Alpha (ethology) Crystallography X-Ray Receptors N-Methyl-D-Aspartate Chemical synthesis Quinolizidines Rats Mice In vivo Drug Discovery Animals Molecular Medicine NMDA receptor Beta (finance) Quinolizines
Zdroj:	Journal of Medicinal Chemistry. 38:2483-2489
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ef324d4752d59b28c371c6e64016ffb3 https://doi.org/10.1021/jm00013a025 Zobrazit plný text záznamu