DOPAMINERGIC BENZO[A]PHENANTHRIDINES - RESOLUTION AND PHARMACOLOGICALEVALUATION OF THE ENANTIOMERS OF DIHYDREXIDINE, THE FULL EFFICACY D-1DOPAMINE-RECEPTOR AGONIST

Racemic oxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine (2, dihydre xidine) was shown previously to be the first bioavailable full efficac y agonist at the D-1 dopamine receptor. In addition to its full D-1 ag onist properties, 2 also is a good ligand for D-2-like dopamine recept ors. The profound anti-Parkinsonian actions of this compound make dete rmination of its enantioselectivity at both D-1 and D-2 receptors of p articular importance. To accomplish this, the enantiomers were resolve d by preparation of diastereomeric (R)-O-methylmandelic acid amides of racemic oxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 4 that wer e then separated by centrifugal chromatography. An X-ray analysis of t he (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute confi guration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-depro tection afforded enantiomeric amines that were then tested for biologi cal activity. In striatal membranes, the (6aR,12bS)-(+)-enantiomer 2 h ad about twice the affinity of the racemate and 25-fold greater affini ty than the (-)-enantiomer at the D-1 receptor labeled by [H-3]SCH2339 0 (K(0.5)s of 5.6, 11.6, and 149 nM, respectively). Similarly, the (+) -enantiomer 2 had about twice the affinity of the racemate for human D -1 receptors expressed in transfected Ltk(-) cells. Functionally, the (+)-enantiomer of 2 was a full agonist, with an EC(50) of 51 nM in act ivating striatal dopamine-sensitive adenylate cyclase versus 2.15 mu M for the (-)-enantiomer. With respect to D-2-like receptors, (+)-2 had a K-0.5 of 87.7 nM in competing with [H-3]spiperone at D-2 binding si tes in rat striatal membranes versus about 1 mu M for the (-)-enantiom er. Together, these data demonstrate that both the D-1 and D-2 activit ies of dihydrexidine reside principally in the (GaR,12bS)-(+)-enantiom er. The results are discussed in the context of structure-activity rel ationships and conceptual models of the D-1 receptor.