Theoretical structure-activity studies of beta-carboline analogs. Requirements for benzodiazepine receptor affinity and antagonist activity.

The techniques of theoretical chemistry have been used to elucidate the molecular properties and modes of receptor binding that modulate receptor affinity and antagonist activity of the beta-carbolines, a class of potent benzodiazepine antagonists. Six analogs were chosen in order to investigate the role of the amine (NH) group, the aromatic nitrogen, and the C3-substituent in determining receptor affinities. Electrostatic potential mapping and characterization of explicit drug-receptor interactions have led to the hypothesis that simultaneous interaction of a model cationic arginine site with the N2 and C3-substituents could play a key role in determining receptor affinities. The electron-withdrawing effects of C3-substituents on the amine nitrogen appear less important, though interactions of these groups with an anionic glutamate or aspartate site could also occur at the receptor. Similarly, stacking interactions with neutral or cationic aromatic residues such as tryptophan or protonated histidine could occur, but do not appear to be determinants of the relative receptor affinity of the beta-carbolines.