Structural determinants of selective affinity for brain D-1 dopamine receptors within a series of 1-phenyl-1H-3-benzazepine analogues of SK&F 38393 and SCH 23390.

A series of 1-phenyl-1H-3 benzazepine analogues of the D-1 agonist SK&F 38393 and of the D-1 antagonist SCH 23390 were compared for their relative abilities to displace the binding of [3H]piflutixol and [3H]spiperone to striatal D-1 and D-2 receptors respectively. The benzazepine analogues varied in substitutions at the 3- and 7-positions which distinguish SK & 38393 from SCH 23390. Substitutions at these positions critically influenced affinity for D-1 receptors over a 2000-fold range but influenced affinity for D-2 receptors over only a 30-fold range. 7-Substituents prominently increased affinity and selectivity for D-1 receptors with a rank order of Br = Cl much greater than CH3 greater than H greater than OH. 3-Methylation had a less marked and less selective action to increase affinity for D-1 receptors. Such structural relationships may aid the definition of the topography of brain D-1 receptors and the development of improved selective agents.