Biomimetic approach to potential benzodiazepine receptor agonists and antagonists

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Abstract
Several .beta.-carbolines, isoquinolines, imidazopyridines and canthin-6-ones prepared in biomimetic fashion were tested for their ability to bind to the rat benzodiazepine receptor. Methyl isoquinoline-3-carboxylate (3a), methyl 6,7-dimethoxyisoquinoline-3-carboxylate (3b), 1-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 .beta.-carboline without loss of activity if the substituents are trigonal and maintain a planar topography. Displacement of the carbonyl group by 2 atoms from the aromatic ring (C) of the .beta.-carboline skeleton caused a marked decrease in binding to the benzodiazepine receptor. Maximum binding affinity of .beta.-carbolines is evidently achieved when the carbonyl group at position 3 is attached directly to the aromatic pyridine ring.