Theoretical structural analyses of tricyclic neuroactive drugs: quantum pharmacologic descriptors for clustering anticonvulsant, antidepressant, and antipsychotic activities

The spatial disposition of the aromatic rings of tricyclic antidepressant, antipsychotic and anticonvulsant drugs has been deemed to be an influential factor in determining their respective pharmacological activity. The present study investigates this hypothesis through a theoretical conformational analysis of representative compounds from each of these neuroactive drug families. Comparative examination of optimized structures generated using molecular mechanic and semiempirical (AM1) molecular orbital techniques has revealed a correlation between the topological descriptors used to define the common tricyclic moiety of these drugs and their biological mode of action. Electronic effects have also been found to be useful in explaining the differential bioactivities. (C) 1999 Elsevier Science B.V. All rights reserved.