Pharmacologic agents for CNS disorders are often inhibitors that occupy receptors, with
frequent unavoidable side effects likely due to continuous binding. This review summarizes
development of a novel aldehyde dehydrogenase 2 (ALDH2) inhibitor that specifically targets unique
drug related episodic surges in dopamine (DA), a pathophysiologic mechanism that appears to
underlie much of drug-seeking behavior. We have synthesized highly selective novel ALDH2
inhibitors (ALDH2i) that block alcohol- and cocaine cue-induced surges in nucleus accumbens (NAc)
DA and prevent reinstatement of alcohol heavy drinking, cocaine self-administration and
reinstatement of cocaine relapse-like behavior. The mechanism of action of ALDH2i depends on
inhibiting dopamine aldehyde (DOPAL) clearance by ALDH2, enabling unmetabolized DOPAL to
condense with DA to generate tetrahydropapaveroline (THP). THP selectively inhibits the activated
(phosphorylated) tyrosine hydroxylase (TH) to suppress DA synthesis. Selective inhibition of ALDH2 appears to have
therapeutic potential for treating cue-induced drug relapse, a major unmet need for treating addicted subjects.
Keywords: Addiction, alcohol, ALDH2, cocaine, craving, relapse.
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