Solution-Phase Parallel Synthesis of N,6-Disubstituted Isoquinuclidines as Ibogaine Analogs

Abstract

The naturally-occurring alkaloid ibogaine, found in the West African shrub Tabernanthe iboga, possesses the ability to diminish self-administration of substances of abuse, such as cocaine, heroin and alcohol. This was the lead structure for the design of a 75-member library of N,6-disubstituted isoquinuclidines. A solution-phase method for their synthesis is described. In a previous study [1], we developed solution-phase small-molecule libraries containing structural analogs of ibogaine (1, NIH 10567, Endabuse™), a natural product isolated from the African shrub Tabernanthe iboga. Ibogaine has been widely studied as a treatment of stimulant dependence [2]. Reviews of the history, chemistry, mechanisms of action, pharmacokinetic properties, metabolism, neurochemical and anti-addictive properties have appeared [2, 3, 4]. Ibogaine possesses the ability to diminish self-administration of cocaine [5] as well as morphine [6] and alcohol [7]. These studies suggest that it may possess therapeutically useful anti-addiction and anti-craving properties, however its use has been restricted because of reports of neurotoxicity [8]. We have attempted to separate the beneficial anti-addictive properties from the neurotoxic effects by preparing various structural analogs of the parent alkaloid. 3-position of the indole has been eliminated while maintaining the N,6-disubstitution pattern present in ibogaine.

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