title: Stereoselective synthesis of a conformationally defined cyclohexyl carnitine analogue that binds CPT-1 with high affinity.
abstract: Carnitine (1, 3-hydroxy-4-trimethylammoniobutyrate) is important in mammalian tissue as a carrier of acyl groups. In order to explore the binding requirements of the carnitine acyltransferases for carnitine, we designed conformationally defined cyclohexyl carnitine analogues. These diastereomers contain the required gauche conformation between the trimethylammonium and hydroxy groups but vary the conformation between the hydroxy and carboxylic acid groups. Here we describe the synthesis and biological activity of the all-trans diastereomer (2), which was prepared by the ring opening of trans-methyl 2,3-epoxycylohexanecarboxylate with NaN3. Racemic 2 was a competitive inhibitor of neonatal rat cardiac myocyte CPT-1 (K(i) 0.5 mM for racemic 2; K(m) 0.2 mM for L-carnitine) and a noncompetitive inhibitor of neonatal rat cardiac myocyte CPT-2 (K(i) 0.67 mM). These results suggest that 2 represents the bound conformation of carnitine for CPT-1.
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham 35294, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Hutchison
authors.forename: A
authors.initials: A
authors.lastname: Saeed
authors.forename: P E
authors.initials: PE
authors.lastname: Wolkowicz
authors.forename: J B
authors.initials: JB
authors.lastname: McMillin
authors.forename: W J
authors.initials: WJ
authors.lastname: Brouillette
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D002478:Cells, Cultured; D010856:Columbidae; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats
chemical_list: C121898:2-hydroxy-3-(trimethylammonio)cyclohexanecarboxylic acid; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D000644:Quaternary Ammonium Compounds; D002334:Carnitine O-Palmitoyltransferase