Dopamine receptor model and its application in the design of a new class of rigid pyrrolo[2,3-g]isoquinoline antipsychotics

Abstract

A hypothetical model of the interaction of antipsychotic drugs with the dopamine receptor is described. This 3-dimensional molecular model was developed on the basis of plausible intermolecular interactions between pharmacophoric groups of diverse types of antipsychotic drugs and postulated amino acid side chain substituents of the receptor protein. Three essential binding sites (1 possibly required for antagonism) and 1 lipophilic auxiliary binding site are identified. The geometry is defined via the 3-dimensional structures of drugs exhibiting receptor activity, including (R)-apomorphine, (+)-dexclamol and molindone (whose crystal structure was determined). A new conformationally rigid pyrrolo[2,3-g]isoquinoline derivative was designed to conform to the receptor model. The compound (.+-.) 1 m (2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g]isoquinolin-4-one; Ro 22-1319) exhibits potent antipsychotic-like activity in rats. The activity is stereospecific, residing in the (-)enantiomer, predicted and confirmed by X-ray crystal structure analysis of (-)-1 .cntdot. HCl to have the 4aR,8aR absolute configuration.