CONFORMATIONAL-ANALYSIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF SELECTIVE DOPAMINE D-1 RECEPTOR AGONISTS AND ANTAGONISTS OF THE BENZAZEPINE SERIES

Comprehensive conformational analysis using molecular mechanics calculations (MM2(85)) has been carried out for the potent and selective dopamine D-l receptor agonist 7,8-dihydroxy-l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine (1; SK&F 38393), the antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine (8; SCH 23390), and several analogues, including conformationally constrained ones. Calculated conformational energies have been related to pharmacological and biochemical data in an attempt to identify the biologically active conformations of 1 and 8. It is concluded that the most probable receptor-bound conformation in both cases is a chair conformation with an equatorial phenyl ring and for 8 an equatorial N-methyl group. It is suggested that the orientation of the phenyl ring in the receptor-bound molecule does not deviate in terms of dihedral angles by more than about 30° from the preferred phenyl group rotamer in which the planes of two aromatic rings are essentially orthogonal. © 1990, American Chemical Society. All rights reserved.