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.