Electrostatic requirements for high benzodiazepine receptor affinity among betacarboline-3-carboxylic acid derivatives.

Electrostatic requirements for high benzodiazepine receptor affinity among C3-substituted betacarbolines have been discussed on the basis of theoretical calculations employing ab initio quantum chemical methods. The molecular electrostatic potentials (MEPs) were evaluated in the plane of the tricyclic ring and at the distance of 160 pm perpendicular to the plane. In the ring plane three distinct minima were found, one in the A-ring and the other two at the nitrogens, for all BCs studied. One or two strong negative areas are also associated with the C3-substituent (COOH, COOR or CN). At the distance of 160 pm a large MEP minimum was found near N2 and the substituent at C3. Lack of either or both of these regions yields a dramatic decrease in their BZ-receptor binding affinity. The electrostatic potential characteristics of the title compounds has led us to suggest an MEP pharmacophore for BCs.