(+)-Hemipalmitoylcarnitinium strongly inhibits carnitine palmitoyltransferase-I in intact mitochondria

• Published in: Journal of medicinal chemistry 1993, Vol.36 (2), p.237-242
• Main Authors: Gandour, Richard D, Leung, On Tai, Greway, Anthony T, Ramsay, Rona R, Nic A Bhaird, Noirin, Fronczek, Frank R, Bellard, Bret M, Kumaravel, G
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Carnitine - metabolism; Carnitine O-Palmitoyltransferase - antagonists & inhibitors; Carnitine O-Palmitoyltransferase - metabolism; Chemistry; Condensed matter: structure, mechanical and thermal properties; Exact sciences and technology; Heart - drug effects; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Liver - drug effects; Liver - enzymology; Male; Mitochondria - drug effects; Mitochondria - enzymology; Myocardium - enzymology; Organic chemistry; Organic compounds; Palmitoylcarnitine - analogs & derivatives; Palmitoylcarnitine - chemical synthesis; Palmitoylcarnitine - pharmacology; Physics; Preparations and properties; Rats; Rats, Sprague-Dawley; Structure of solids and liquids; crystallography; Structure of specific crystalline solids
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00054a007

The reaction of the methyl ester of (R)-norcarnitine with 1-bromo-2-heptadecanone produces (+)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, 3, which hydrolyzes to (+)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, HPC) upon treatment with aqueous sodium hydroxide. Single-crystal X-ray analyses have confirmed the structures of (+)-HPC and 3. (+)-HPC inhibits carnitine palmitoyltransferase (CPT-I) activity for the forward reaction (palmitoyl-CoA + carnitine-->) in intact mitochondria from rat heart and rat liver. (+)-HPC competitively (versus carnitine) inhibits CPT-I activity in both rat heart and liver mitochondria with Ki = 2.8 +/- 0.5 and 4.2 +/- 0.7 microM, respectively. As one of the strongest specific inhibitors of CPT-I, HPC is a potential therapeutic agent in myocardial ischemia and Type II diabetes.