STRUCTURE-ACTIVITY-RELATIONSHIPS IN THE TRANS-HEXAHYDROINDOLO[4,3-AB]PHENANTHRIDINE (BENZERGOLINE) SERIES .2. RESOLUTION, ABSOLUTE-CONFIGURATION, AND DOPAMINERGIC ACTIVITY OF THE SELECTIVE D(1) AGONIST CY-208-243 AND ITS IMPLICATION FOR AN EXTENDED ROTAMER-BASED DOPAMINE RECEPTOR MODEL

4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines (''benzergolines'') was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved and both enantiomers oxidized to the final products. The biological activity was found to reside entirely in the (-)-enantiomer, (-)-1 (CY 208-243). An X-ray study of its (-)-mandelic acid salt revealed a 6aR,12bR absolute configuration, which, in confirmation of the structure hypothesis, corresponds to that of the ergolines. Unexpectedly, an axial conformation of the N-methyl group was observed in the crystal structure. In contrast, subsequently analyzed crystals of the free base of (-)-1 revealed an equatorial conformation of the N-methyl group, which, we assume, represents the bioactive conformation. Based on the determined absolute configuration, (-)-1 could be oriented in a previously described ''rotamer-based dopamine receptor model'', which allowed the localization of a ''subtype selectivity-inducing site'' (aryl binding site at the D1 receptor, steric barrier at the D2 receptor), marked by the conformationally fixed ''additional'' phenyl group of the benzergoline molecule.