The structure of psychotropic drugs (including theoretical prediction of a new class of effective neuroleptics)

Abstract

A brief introductory review is presented of the etiology of affective disorders, the neuropsychopharma-cological modalities used in treating these states, and the mechanisms by which these therapies act. The topological and topographical requisites for effective neuroleptic (antipsychotic) drugs (the major tranquillizers) are outlined. Quantum chemical results, both CNDO/2 and INDO, are presented for promazine, perazine, and their CI and CF3 derivatives. Application of the topographical postulates led us to perform quantum chemical calculations on a series of hitherto unsynthesized and untested compounds, N-piperdinopromazines. We predicted these would be effective neuroleptics. In the interim a compound of this type was synthesized and tested and it is, indeed, a major tranquillizer. The subtle differences in geometrical conformation between tricyclic neuroleptics (which are postsynaptic dopamine blockers) and the closely related tricyclic antidepressants (which inhibit reuptake of norepinephrine and serotonin back into the the presynapse) are indicated. In the area of hallucinogens or psychotomimetic agents, it is emphasized that even though compounds like LSD and mescaline exhibit cross tolerance, they apparently do not act by the same mechanism. Thus the commonalities in structures between these two groups previously invoked by other authors merit reexamination and a sharpening of focus. Quantum chemical results, CNDO/2 and PCILO, are presented for a few of these compounds whose crystal structures have been determined recently. Our interest in these psychotomimetics was twofold; first, because of their intrinsic interest in the hierarchy of psychotropic drugs and second, to gain insight into why many narcotic antagonists are undesirably psychotomimetic.