Latent inhibitors of aldehyde dehydrogenase as alcohol deterrent agents.
A series of compounds structurally related to pargyline (N-methyl-N-propargylbenzylamine, 4) were synthesized with the propargyl group replaced by a cyclopropyl, allyl, or 2,2,2-trichloroethyl group and, additionally in several cases, with the methyl group replaced by H. The rationale for their preparation was based on the expectation that, like pargyline, which gives rise to propiolaldehyde, oxidative metabolism of the above compounds by the hepatic cytochrome P-450 enzymes would lead to the generation in vivo of the aldehyde dehydrogenase (AlDH) inhibitors, cyclopropanone, acrolein, or chloral. These compounds were evaluated for inhibition of liver AlDH in vivo by measuring the elevation of ethanol-derived blood acetaldehyde in rats and in vitro by the rate of oxidation of acetaldehyde by intact and osmotically disrupted liver mitochondria. Administration of N-methyl-N-cyclopropylbenzylamine (5) and its nor-methyl analogue (8) to rats raised blood acetaldehyde levels significantly over controls at 2 h. This effect was more pronounced at 9 h, with blood acetaldehyde levels reaching 19 to 27 times control values and approaching the values induced by pargyline. Other compounds elicited significant elevations in ethanol-derived blood acetaldehyde only at 9 h. We suggest that latent inhibitors of AlDH such as 5 or 8 might be useful as alcohol deterrent agents.
D000437:Alcoholism / Q000188:drug therapy*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D000431:Ethanol / Q000097:blood; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008930:Mitochondria, Liver / Q000201:enzymology; D010293:Pargyline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000431:Ethanol; D010293:Pargyline; D000444:Aldehyde Dehydrogenase