Abstract
A novel two step protocol was developed to gain regiospecific access to 3-substituted β- and aza-β-carbolines, 3-PBC (1), 3-ISOPBC (2), βCCt (3), 6-aza-3-PBC (4) and 6-aza-3-ISOPBC (5). These β-carbolines (1-3) are potential clinical agents to reduce alcohol self-administration, especially 3-ISOPBC·HCl (2·HCl) which appears to be a potent anti-alcohol agent active against binge drinking in a rat model of maternally deprived (MD) rats. The method consists of two consecutive palladium-catalyzed reactions: a Buchwald-Hartwig amination followed by an intramolecular Heck-type cyclization in high yield.
Highlights
Introduction βCarbolines, aza-β-carbolines and their derivatives are important targets in synthetic chemistry.1 In addition, they are found in a large number of natural products, many of which demonstrate novel biological activity, especially in regard to the reduction of alcohol self-administration [binge drinking (BD)]
3-PBC·HCl significantly reduced alcohol self-administration and reduced craving in baboons.26 β-Carbolines 1·HCl and 3 displayed mixed weak agonist-antagonist profiles in vivo in alcohol preferring (P) and high alcohol drinking (HAD) rats.18,26–28. In addition to their use to study the molecular basis of alcohol reinforcement, α1 Bz β-carboline ligands which display mixed pharmacological antagonistagonist activity in alcohol P and HAD rats may be capable of reducing alcohol intake while eliminating or greatly reducing the anxiety associated with habitual alcohol, abstinence or detoxification
It was envisioned that the core structure of 3,6-disubstituted β-carboline A could be obtained from diarylamine B via an intramolecular Heck cyclization and it was anticipated that diarylamine B could arise from a substituted aniline C and a substituted pyridine derivative D via a Buchwald–Hartwig amination (Scheme 3)
Summary
Introduction β-Carbolines, aza-β-carbolines and their derivatives are important targets in synthetic chemistry.1 They are found in a large number of natural products, many of which demonstrate novel biological activity, especially in regard to the reduction of alcohol self-administration [binge drinking (BD)]. In addition to their use to study the molecular basis of alcohol reinforcement, α1 Bz β-carboline ligands which display mixed pharmacological antagonistagonist activity in alcohol P and HAD rats may be capable of reducing alcohol intake while eliminating or greatly reducing the anxiety associated with habitual alcohol, abstinence or detoxification.18,28–30 These types of ligands may be ideal clinical agents for the treatment of alcohol dependent individuals 3-PBC·HCl significantly reduced alcohol self-administration and reduced craving in baboons. β-Carbolines 1·HCl and 3 displayed mixed weak agonist-antagonist profiles in vivo in alcohol preferring (P) and high alcohol drinking (HAD) rats. in addition to their use to study the molecular basis of alcohol reinforcement, α1 Bz β-carboline ligands which display mixed pharmacological antagonistagonist activity in alcohol P and HAD rats may be capable of reducing alcohol intake while eliminating or greatly reducing the anxiety associated with habitual alcohol, abstinence or detoxification. these types of ligands may be ideal clinical agents for the treatment of alcohol dependent individuals
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