Biomimetic approach to potential benzodiazepine receptor agonists and antagonists.
Several beta-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, 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. Moreover, displacement of the carbonyl group by two atoms from the aromatic ring (C) of the beta-carboline skeleton caused a marked decrease in binding to the benzodiazepine receptor. This observation supports the hypothesis that maximum binding affinity of beta-carbolines is achieved when the carbonyl group at position 3 is attached directly to the aromatic pyridine ring.
D000818:Animals; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D007202:Indicators and Reagents; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D003975:Diazepam