Studies directed toward the synthesis and pharmacological evaluation of certain substituted trans-fused hexahydrobenzo(a)phenanthridines including the resolution of the enantiomers of dihydrexidine

Timm Allen Knoerzer, Purdue University

Abstract

In an effort to explore the spatial limits of the pendent phenyl accessory binding domain, a series of $\beta$-phenyl-substituted analogs of $(\pm)$-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo (a) phenanthridines was synthesized and their biological profiles were determined. Furthermore, in order to explore the stereochemical environment of the D$\sb1$ receptor, the enantiomers of dihydrexidine were chemically resolved and evaluated. $(\pm)$-Trans-2-methyl-10,11-dihydroxy-5,6,6a,7,8,$ 12$b-hexahydrobenzo (a) phenanthridine has been found to be a highly potent (EC$\sb{50}$ of 360 nM) and selective (36-fold for D$\sb1$ over D$\sb2)$ agonist for the D$\sb1$ receptor. This compound represents a significant improvement in receptor subtype-selectivity without loss of high intrinsic activity. In addition, each of the pendent phenyl-substituted analogs, with the exception of the 2-Ph analog, exhibited a pharmacological profile similar to that of the parent compound, DHX. Each analog has been shown to be a high potency, full efficacy agonist with moderate selectivity for the D$\sb1$ receptor. It is apparent from the results that the D$\sb1$ receptor can tolerate small group substitutions in the 2-, 3-, and 4-positions of the pendent phenyl ring. In an effort to produce D$\sb2$ selective ligands, the N-n-propyl analogs of 3-Me, 4-Me, and 4-I DHX were synthesized. The 4-I and 4-I N-propyl compounds have yet to be evaluated. These compounds were conceptualized following a pharmacological evaluation of the nonalkylated congeners. The 3-Me and 4-Me dihydrexidine analogs exhibited unusually high affinity for the D$\sb2$ receptor (43 and 39 nM), in addition to the expected high affinity for the D$\sb1$ receptor (10 and 13 nM). The 3-Me N-propyl compound maintained its high D$\sb2$ affinity (11 nM), while the D$\sb1$ affinity significantly decreased (369 nM). Surprisingly, 4-Me N-propyl DHX exhibited high affinity for both the D$\sb1$ and D2 receptors (49 nM and 48 nM). It has been shown that this compound is actually a selective D$\sb3$ ligand (110-fold selectivity for the D$\sb3$ over D$\sb2).$ In order to assess the bioactivity of the individual isomers of dihydrexidine, the enantiomers were chemically resolved and their biological profiles were determined. As predicted, the high D$\sb1$ and D$\sb2$ affinity, as well as the high intrinsic activity expressed by dihydrexidine, reside in the (6aR, 12bS)-(+)-enantiomer. It is apparent from these results that a stereochemical requirement for binding to the D$\sb1$ receptor possibly exists.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Pharmacology|Organic chemistry

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