We are designing, preparing, and assaying conformationally rigid inhibitors of carnitine octanoyltransferase (CAT), carnitine octanoyltransferase (COT), and carnitine palmitoyltransferase (CPT), enzymes that catalyze acyl transfer between carnitine and coenzyme A (CoA). The primary aim of the proposed work is to identify the topographical arrangement of the four key recognition sites on these enzymes by comparing inhibition constants (Ki's) of a series of rigid, cyclic analogs. Our long-range goal is to map the pattern of molecular recognition in these enzymes. Identifying the molecular interactions will lead to a better understanding of the physiological chemistry and, more specifically, regulation of the enzymes. Carnitine has critical functions in the overall oxidation of fatty acids for the generation of energy. Specifically it is required for the transport of long-chain fatty acids across the inner mitochondrial membrane. Because of this, our inhibitors have potential therapeutic value in diabetes, ischemia, and drug delivery. Insulin deficiency leads to ketosis. CPT is the rate-limiting enzyme in ketogenesis and thus CPT inhibitors are anti-ketotics in diabetes. Ischemia causes an increase in acylcarnitines, which alter the activity of sodium, potassium ATPase and calcium ATPase. CPT inhibitors can alter metabolic dysfunction to improve myocardial function in the ischemic heart. Acylcarnitines enhance membrane permeability for a variety of poorly absorbing drugs. The proposed molecules or isomers of acylarnitines, could function as drug absorption enhancing agents. Preliminary results show that our meso-2,6(biscarboxymethyl)-4,4- dimethylmorpholinium bromide inhibits gluconeogenesis in rat hepatocytes. As such, it may be useful as a hypoglycemic agent in the treatment of diabetes. These results bode well for the pharmacological potential of our proposed inhibitors.
