Chemical Synthesis and Biological Evaluation of 18-Methoxycoronaridine (18-MC) as a Potential Anti-addictive Agent

Abstract

Ibogaine (1a), one of the psychoactive indole alkaloids found in the root bark of the West African shrub, Tabernanthe iboga, has purported efficacy in treating multiple forms of drug abuse. A single oral treatment with ibogaine or its salts, in the doses of 6 to 19 mg / kg, or a series of four treatments may, respectively, eliminate addictive behavior for up to 6 months or three years In rats, ibogaine (40 mg / kg) decreases intravenous self-administration of both morphine and cocaine and oral self-administration of ethanol and nicotine. However, ibogaine also exerts several serious side effects including tremors, toxic degeneration of Purkinje cells in the brain and an acute depressant effect on responding for water in rats. Such side effects may restrict the use of ibogaine to treat human addictive disorders. These problems led us to develop novel synthetic ibogaine congeners that mimic ibogaines therapeutic profile, but without side effects. 18-Methoxycoronaridine (18-MC, 2c), a novel iboga alkaloid congener, has been synthesized and evaluated as a potential anti-addictive agent. Racemic 18-MC has been synthesized in 13 steps, with overall 7percent yield. Both enantiomers of 18-MC have been obtained, either by chemical resolution of (plus minus)-18-MC or by enantioselective total synthesis using chiral auxiliaries. Like ibogaine, 18-MC decreases the intravenous self-administrat ion of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats. However, 18-MC does not evidence ibogaines side effects. Thus, 18-MC has potential as a safe and effective treatment for multiple forms of drug abuse.