Suppression of Heavy Drinking and Alcohol Seeking by a Selective ALDH‐2 Inhibitor

Abstract

Our findings suggest that selective reversible ALDH-2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics.

Discovery of a Novel Class of Covalent Inhibitor for Aldehyde Dehydrogenases

“…The same screening procedure also led to the identification of several inhibitors. Inhibitors of ALDH family members have potential application in alcohol dependence (12), cocaine addiction (13), anxiety (14), and as resensitizing agents for cancers that are resistant to the cyclophosphamide class of compounds (15)(16)(17). In this latter regard, siRNA knockdown of ALDH1A1 and/or ALDH3A1 increased sensitivity to cyclophosphamide, with the double knockdown demonstrating the greatest resensitization (5).…”

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

“…Inhibition of ALDH2 suppresses cocaine-seeking behavior in conditioned rats through a 3,4-dihydroxyphenylacetaldehyde-dependent decrease in dopamine synthesis (Yao et al, 2010). Likewise, ethanol consumption by rodents has been shown to be reduced by ALDH inhibitor treatment through a mechanism independent of increases in systemic levels of acetaldehyde (Keung et al, 1995) and potentially involving suppression of central dopamine release (Arolfo et al, 2009). Such a central nervous system mechanism may contribute to the low incidence of alcohol consumption/addiction observed in subjects harboring the ALDH2*2 genetic variant that encodes the inactive FIG.…”

“…For example, CVT-10216 (Fig. 8) shows an IC 50 of 29 nM for ALDH2 and 1300 nM for ALDH1 (Arolfo et al, 2009). An additional advantage of these inhibitors is their minimal effect on monoamine oxidase (Yao et al, 2010).…”

From Herbal Roots to Synthetic Medicines: A Historical Perspective

“…A major step forward in this journey is the article in the November 2009 issue of Alcoholism Clinical and Experimental Research (ACER), the result of collaborative research from multiple laboratories in the United States and Australia, and orchestrated by Ivan Diamond from CV Therapeutics (now Gilead) in Palo Alto, CA (Arolfo et al, 2009). Based on the X-ray crystal structure of daidzin in complex with human ALDH2 (Lowe et al, 2008), more potent and selective ALDH2 inhibitors were synthesized.…”