Comparison of (+)- and (-)-hemipalmitoylcarnitinium as inhibitors of hepatic mitochondrial carnitine palmitoyltransferases in diabetic rats.

Abstract

The syntheses of (R)- and (S)-norcarnitine ethyl esters are described starting with an optimized, chiral chemical reduction of ethyl 4-chloroacetoacetate followed by azide substitution, reduction, and dimethylation. The reaction of (R)- and (S)-norcarnitine ethyl esters with 1-bromoheptadecan-2-one gives (+)- and (-)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, respectively, which hydrolyzes to (+)- and (-)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, (+)- and (-)-HPC), respectively, upon treatment with a hydroxide resin. (+)- and (-)-HPC are reversible active-site directed inhibitors of hepatic mitochondrial CPTs. Both stereoisomers inhibit CPT I and CPT II in control and streptozotocin diabetic rat to the same extent (Imax=100%). Using intact mitochondria (CPT I), I50values for (-)-HPC and (+)-HPC were 15.5 microM and 47.5 microM, respectively. The I50 values for CPT II were 6.7 microM and 38.5 microM for (-)-HPC and (+)-HPC, respectively. The mode of inhibition was uncompetitive for CPT I with respect to acyl-CoA. The apparent K(i) for (-)-HPC is about 5 microM. These data suggest that (-)-HPC may be useful for further evaluation as an antidiabetic agent.