Synthesis and evaluation of 3-substituted 17-methylmorphinan analogs as potential anticonvulsant agents

Dextromethorphan (1,(+)-3-methoxy-17-methylmorphinan) demonstrates anticonvulsant activity in a variety of in vitro and in vivo models of convulsive action. It is well known that 1 is metabolized to its phenolic derivative dextrorphan (2) and this metabolite is also a potent anticonvulsant. A series of (+)-3-substituted-17-methylmorphinans, which are structurally similar to 1 but are either not expected to be metabolized to 2 or might do so at a reduced rate, as compared to 1, were prepared. Three analogs, 5 ((+)-3-amino-17-methylmorphinan), 14 ((+)-3-ethoxy-17-methylmorphinan), and 15 ((+)-3-(2-propoxy)-17-methylmorphinan) were found to possess potent anticonvulsant activity with full efficacy (ED50 25, 5.6, and 3.9 mg/kg, sc, respectively) in the rat supramaximal electroshock (MES) test. Binding potencies of these compounds to receptor sites labeled with [3H]dextromethorphan ([3H]1), in rat brain and guinea pig brain subcellular fractions, and [3H]thienylcyclohexylpiperidine (TCP) and [3H]glycine in rat brain, were determined. Most of the analogs displaced [3H]1 from its binding sites, with compounds 14 (IC50 0.42 microM) and 15 (IC50 0.88 microM) having equivalent potencies to 1 (IC50 0.59 microM), in rat brain, and no appreciable activity at the [3H]TCP or [3H]glycine-labeled sites. Compound 5 did not bind with appreciable activity to the [3H]1 site, in rat brain, but did bind to the [3H]TCP site with lower potency than the parent 1 (IC50 7.8 and 2.0 microM, respectively). The mechanism of anticonvulsant action of these agents is not clear although it appears that interaction at the [3H]1 sites may be involved.