Studies directed toward the synthesis of certain trans -fused benzo(a)phenanthridines as structurally rigid dopamine D-1 agonists and antagonists
Abstract
In an effort to develop dopamine receptor subtype-selective ligands, certain 10,11-disubstituted and 11-monosubstituted $(\pm)$-trans-5,6,6a,7,8,12b-hexahydrobenzo (a) -phenanthridines were synthesized. The synthesis of each series began by condensing the appropriately substituted $\beta$-tetralone with benzylamine and then treating the resulting enamine with benzoyl chloride. The enamide products were photocyclized, and the resulting lactams were reduced with diborane. Following catalytic N-debenzylation, the secondary amines were appropriately N-alkylated and/or ether deprotected. The 11-hydroxy-6-methylbenzo (a) phenanthridine was further brominated to provide the 10-bromo derivative. The target compounds were all characterized and, in certain cases, subsequently evaluated in the usual biochemical assays for dopamine-like activity. $(\pm)$-Trans-10,11-Dihydroxy-5,6,6a,7,$ 8,$12b-hexahydrobenzo (a) phenanthridine (dihydrexidine) has been found to be a highly potent (EC$\sb{50}$ of approximately 70 nM in activating dopamine-sensitive rat striatal adenylate cyclase) and selective (ten-fold selectivity for D-1 over D-2 receptors) agonist at the dopamine D-1 receptor in rat brain. N-Methylation of the parent compound decreased affinity for D-1 sites about 7- to 8-fold, and markedly decreased its ability to stimulate adenylate cyclase. Addition of an N-n-propyl group reduced affinity for D-1 sites by about fifty-fold, and essentially abolished ability to stimulate adenylate cyclase. However, this latter derivative had twice the affinity of the selective D-2 agonist quinpirole for the D-2 receptor. The N-allyl derivative of dihydrexidine and $(\pm)$-trans-10,11-methylenedioxy-5,6,6a,7,$ 8,$12b-hexahydrobenzo (a) -phenanthridine, a putative prodrug of dihydrexidine, have been synthesized similarly, but they have not yet been pharmacologically evaluated. Likewise, the monohydroxybenzo (a) phenanthridines have not yet been tested. The available biological results are discussed in the context of a conceptual model for the agonist state of the D-1 receptor. A novel feature of this dopamine receptor model is the description of a site complementary to a phenyl ring situated at the $\beta$-position of the ethylamine side chain and nearly coplanar with the catechol ring. This phenyl accessory region is derived from the intrinsic activity and selectivity of the title benzo (a) phenanthridines, relative to the phenylbenzazepines, phenyltetrahydroisoquinolines and other dopaminergic classes.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.