A new polyamine derivative, a structural analog of spermine, with in vivo activity as an inhibitor of ethanol appetite.
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, 20 mg/kg, p.o., 3 days), 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., 60 days) 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.
Font
María
M
Modelización Molecular, Departamento de Química Orgánica y Farmacéutica, Universidad de Navarra, Irunlarrea no. 1, E-31008 Pamplona, Spain. mfont@unav.es
Sanmartín
Carmen
C
García
Hernán
H
Contreras
Selfa
S
Paeile
Carlos
C
Bilbeny
Norberto
N
D000427:Alcohol Deterrents / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared
D000427:Alcohol Deterrents; D003510:Cyclohexanes; C504396:N,N'-bis-(3-aminopropyl)cyclohexane-1,4-diamine, tetramethanesulfonate; D011073:Polyamines; D000431:Ethanol