FURTHER DEFINITION OF THE D-1 DOPAMINE-RECEPTOR PHARMACOPHORE - SYNTHESIS OF 8,9,13B-HEXAHYDRO-5H-BENZO[D]NAPHTH[2,1-B]AZEPINES AS RIGID ANALOGS OF BETA-PHENYLDOPAMINE

In an effort to define further the active geometry of the beta-phenyld opamine pharmacophore of certain dopamine D1 agonists, the title compo unds have been synthesized as conformationally restricted homologues o f the potent benzophenanthridine dopamine D1 agonist dihydrexidine 4a, The dihydroxy secondary amine 5b was evaluated as a potential agonist , whereas the N-methyl compounds 5a and 5c were hypothesized to be ant agonists, Surprisingly, none of the three compounds had high affinity for dopamine D1 or D2 receptors. A comparison of the low-energy confor mations of these molecules shows that the pendant phenyl ring of 5b is twisted about 28 degrees relative to that of the corresponding ring o f 4a. Further, the additional methylene used to expand the C ring of 5 b projects toward the a face of the molecule, perhaps suggesting that steric protrusion in this region of the molecule is not tolerated. Fin ally, the phenethylamine fragment incorporated into these molecules de viates about 30 degrees from the antiperiplanar conformation postulate d to be necessary for agonist activity, On the other hand, the potenti al antagonist molecules 5a and 5c were compared with the dopamine D1 a ntagonist SCH 39166 2. The conformations of the former two structures differ quite dramatically from that of 2. The most notable differences lie in the relative orientations of the pendant phenyl rings in the t wo series, as well as the fact that the ethylamine fragment in 2 appro ximates a gauche conformation, while the comparable orientation in 5a and 5c more nearly approaches an antiperiplanar conformation. These fi ndings will be used to refine further the model of the dopamine D1 ago nist receptor that we have previously developed.