ADENOSINE KINASE INHIBITORS

Adenosine (ADO) is an endogenous modulator of intercellular signaling that provides homeostatic reductions in cell excitability during tissu e stress and trauma. The inhibitory actions of ADO are mediated by int eractions with specific cell-surface G-protein coupled receptors regul ating membrane cation flux, polarization, and the release of excitator y neurotransmitters. ADO kinase (AK; EC 2.7.1.20) is the key intracell ular enzyme regulating intra- and extracellular ADO concentrations. In hibition of AK produces marked increases in extracellular ADO levels t hat are localized to cells and tissues undergoing accelerated ADO rele ase. Thus AK inhibiton represents a mechanism to selectively enhance t he protective actions of ADO during tissue trauma without producing th e nonspecific effects associated with the systemic administration of A DO receptor agonists. During the last 10 years, specific inhibitors of AK based on the endogenous purine nucleoside substrate, ADO, have bee n developed. Potent AK inhibitors have recently been synthesized that demonstrate high specificity for this enzyme as compared to other ADO metabolic enzymes, transporters, and receptors. In both in vitro and i n vivo models, AK inhibitors have been shown to potently increase ADO concentrations in a tissue and event specific fashion and to demonstra te potential clinical utility in animal models of epilepsy, ischemia, pain, and inflammation. AK inhibitors have demonstrated superior effic acy in these models as compared to other mechanisms of modulating ADO availability, and these agents exhibit reduced side-effect liabilities compared to direct acting ADO receptor agonists. The preclinical prof ile of AK inhibitors indicate that these agents may have therapeutic u tility in a variety of central and peripheral diseases associated with cellular trauma and inflammation. Clinical trials are currently under way to evaluate the efficacy of AK inhibitors in seizure disorders and pain.