A new polyamine derivative, a structural analog of spermine, with in vivo activity as an inhibitor of ethanol appetite

Abstract

This report describes the design and synthesis of the synthetic polyamine DCD (N,N′-bis-(3-aminopropyl)cyclohexane-1,4-diamine, tetramethanesulfonate), a structural analog of spermine, and its in vivo activity as an inhibitor of alcohol consumption in a free-paradigm carried out on genetically high-ethanol-consuming UChB rats. After acute treatment with DCD (daily single dose, 20mg/kg, p.o., 3days), a 19% decrease in ethanol intake was obtained, without affecting the levels of food and water intake. After chronic treatment (daily single dose, 20mg/kg, p.o., 60days) a decrease of up to 60% in ethanol intake with respect to the basal period was provoked; this effect was significantly maintained during the post-treatment period and, according to the data obtained from the determination of acetaldehyde levels in blood, was not related to a possible disulfiram-like effect. The design of this new compound was carried out using molecular modeling techniques, with the structures of natural polyamines (putrescine, spermidine, and spermine) and biosynthetically related diamines (1,3-diaminopropane; DAP) as templates. These polyamines have shown activity as inhibitors of ethanol appetite in the same experimental model.