Synthesis and Biological Evaluation of a Series of Substituted Benzo[a]phenanthridines as Agonists at D1 and D2 Dopamine Receptors

Abstract

Dihydrexidine [4;(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8, 12b-hexahydrobenzo[a]phenanthridine (DHX)], the first high-affinity full D1 agonist, also is known to have significant D2 activity. The present work reports the synthesis and pharmacological activity of a series of analogs substituted in the pendent phenyl ring (i.e., 2-, 3-, or 4-position). (+/-)-trans-2-Methyl-10,11-dihydroxy-5,6,6a,7,8, 12b-hexahydrobenzo[a]phenanthridine (5) was a high-affinity D1 agonist, having approximately 4-fold greater D1 vs D2 selectivity than DHX itself. All of the analogs containing a methyl or ethyl (but not a phenyl) substituent at the 2-, 3-, or 4-position had a pharmacological profile similar to that of the lead compound DHX (4). Each analog was found to be a high-affinity full agonist with moderate selectivity for the D1 receptor. It is apparent from these results that the D1 receptor can tolerate small substituents at the 2-, 3-, and 4-positions of the pendent phenyl ring. On the basis of earlier studies showing that N-alkylation increases D2 selectivity, the 3-methyl N-n-propyl and 4-methyl N-n-propyl compounds 11 and 13 were synthesized. While these analogs exhibited much higher affinity for the D2 receptor, surprisingly 4-methyl-N-propyl-DHX (13) exhibited high affinity for both the D1 and D2 receptors. It was subsequently established that this compound is a selective D3 ligand (110-fold selectivity for the D3 over D2 receptor). The results from these studies demonstrate that several of the hexahydrobenzo[a]phenanthridine derivatives are agonists with high intrinsic activity that may serve as powerful tools to explore the structural features that determine affinity and selectivity (relative to the D2 receptor) of drugs for D1 receptors.

Tolerance to the procholinergic action of the D1 receptor full agonist dihydrexidine

“…To this end, the role of D5 receptors in the stimulatory effects of DHX on hippocampal ACh efflux has not been studied as it has been studied for the D1 receptor partial agonist SKF 38393 (see Laplante et al 2004), where it was shown that its stimulatory effects on ACh release in the hippocampus were prevented in D5 receptor knockout mice. DHX has been shown to bind to DA D2 receptors, where it functions as an agonist in vitro (Brewster et al 1990;Knoerzer et al 1995) and, at high doses, in vivo (see, e.g., Darney et al 1991). This is the reason why we first showed that the stimulatory effects of the 18-mg/kg dose of DHX (which we used in the chronic studies) on hippocampal ACh release were completely abolished by SCH 23390 (see above).…”

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D2Receptors Linked to Adenylate Cyclase

“…Concomitant D 1 activation is also unlikely to play a role. For example, although DHX is a D 1 full agonist, PrDHX is a low intrinsic activity partial D 1 agonist (Knoerzer et al, 1995). Therefore, one would expect very different functional patterns if D 1 receptors were critical to the current phenomena (cf.…”

Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

“…Extension of the hydrophobic bulk to an ethyl group (compound 5b ) incurred an even greater loss of D 1 affinity (D 1 K i = 185 nM) compared to 2 . Although the ethyl substituted analog of DHX (compound 4 ) also displayed affinity lower than the unsubstituted compound [19], its chroman isostere 5b clearly shows a more dramatic negative effect of the ethyl substituent on affinity.…”

“…In the DHX series, substitution on the β-phenyl ring at the 2-position with methyl and ethyl groups gave ligands with increased D 1 selectivity as a result of decreased D 2 affinity [19] (Figure 2). We hypothesized that compounds with analogous substitution at the 11-position of 2 would display D 1 -selectivity greater than the parent compound.…”