Biomimetic Approach to Potential Benzodiazepine. Receptor Agonists and Antagonists

Filadelfo Guzman, Michael Cain, Paul Larscheid, Tim Hagen, James M. Cook, Margaret Schweri, Phil Skolnick, Steven M. Paul

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Several β-carbolines, isoquinolines, imidazopyridines, and canthin-6-ones prepared in biomimetic fashion were tested for their ability to bind to the benzodiazepine receptor. Methyl isoquinoline-3-carboxylate (3a), methyl 6,7-dimethoxyisoquinoline-3-carboxylate (3b), l-phenyl-3-carbomethoxyimidazopyridine (6b), and canthin-6-one (13a) bound with moderate affinities, while 2-carbomethoxycanthin-6-one (13b) bound to benzodiazepine receptors with an affinity comparable to several pharmacologically active benzodiazepines. The potency of 13b suggests that the benzodiazepine receptor(s) can tolerate substitution at positions 1 and 9 of a β-carboline without loss of activity if the substituents are trigonal and maintain a planar topography. Moreover, displacement of the carbonyl group by two atoms (17) from the aromatic ring (C) of the β-carboline skeleton caused a marked decrease in binding to the benzodiazepine receptor. This observation supports the hypothesis that maximum binding affinity of/3-carbolines is achieved when the carbonyl group at position 3 is attached directly to the aromatic pyridine ring.

Original languageEnglish
Pages (from-to)564-570
Number of pages7
JournalJournal of Medicinal Chemistry
Volume27
Issue number5
DOIs
StatePublished - May 1984

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