title: 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.
authors.affiliation: Department of Chemistry (MC 0212) Virginia Tech, Blacksburg, VA, USA.
authors.forename: Prashant S
authors.initials: PS
authors.lastname: Savle
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Neptune
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yang
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Rouden
authors.forename: Brett L
authors.initials: BL
authors.lastname: Kite
authors.forename: Eko W
authors.initials: EW
authors.lastname: Sugandhi
authors.forename: Richard V
authors.initials: RV
authors.lastname: Macri
authors.forename: Khosrow
authors.initials: K
authors.lastname: Kashfi
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gandour
mesh_terms: D000818:Animals; D001665:Binding Sites; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D004195:Disease Models, Animal; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D008968:Molecular Conformation; D010172:Palmitoylcarnitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C058207:hemipalmitoylcarnitinium; D010172:Palmitoylcarnitine; D002334:Carnitine O-Palmitoyltransferase