Synthesis and Evaluation of 3-Substituted 17-Methylmorphinan Analogs as Potential Anticonvulsant Agents

Article abstract of DOI:10.1021/jm00100a019

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 μM) and 15 (IC50 0.88 μM having equivalent potencies to 1 (IC50 0.59 μM), 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 μM, 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.