ABSTRACT
The development of clomipramine represents a combination of rational drug discovery at a preclinical level and clinical serendipity. At the time of the drug's development, elBA had introduced the first tricyclic antidepres-
sant, imipramine, and Geigy had introduced two structurally and therapeutically related drugs, opipramol and desipramine. Thus, antidepressant effects associated with the iminodibenzyl nucleus were clinically established, and the major remaining psychopharmacological goal for this structural series was therapeutic optimization. The specific approach employed in the case of clomipramine rested on structural analogy with the phenothiazine nucleus. The iminodibenzyl and phenothiazine ring structures are similar, and prior demonstration that addition of a three-position chlorine to the latter transformed a sedative antihistamine to a specific antipsychotic made the homologous substitution of particular interest. Structurally, clomipramine is to imipramine what chlorpromazine is to promazine.
