Stereoselective synthesis of a conformationally defined cyclohexyl carnitine analogue that binds CPT-1 with high affinity

Carnitine (1, 3-hydroxy-4-trimethylammoniobutyrate) is important in mammali an tissue as a carrier of acyl groups. In order to explore the binding requ irements of the carnitine acyltransferases for carnitine, we designed confo rmationally defined cyclohexyl carnitine analogues. These diastereomers con tain the required gauche conformation between the trimethylammonium and hyd roxy groups but vary the conformation between the hydroxy and carboxylic ac id groups. Here we describe the synthesis and biological activity of the al l-trans diastereomer (2), which was prepared by the ring opening of trans-m ethyl 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 represen ts the bound conformation of carnitine for CPT-1. (C) 1999 Published by Els evier Science Ltd. All rights reserved.