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

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 treatm...

Full description

Saved in:
Bibliographic Details
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
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00054a007