Therapeutic potential of adenosine kinase inhibitors

Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra and extracellular concentrations of adenosine (ADO), an endogenous m odulator of intercellular signalling that reduces cell excitability during tissue stress and trauma. The inhibitory effects of ADO are mediated by int eractions with specific cell-surface G-protein coupled receptors (GPCR), wh ich regulate membrane cation flux, membrane polarisation and the release of excitatory neurotransmitters. Inhibition of AK potentiates local extracell ular ADO levels at cell and tissue sites which are undergoing accelerated A DO release. Thus, AK inhibition represents a mechanism to selectively enhan ce the endogenous protective actions of ADO during cellular stress while po tentially minimising the non-specific effects associated with the systemic administration of ADO receptor agonists. Novel, potent AK inhibitors have r ecently been synthesised that demonstrate high-specificity for this particu lar enzyme as compared to other ADO metabolic enzymes, transporters and rec eptors. AK inhibitors have been shown to increase ADO concentrations in var ious systems in vitro, as well as in an in vivo model of neurotoxicity. In addition, AK inhibitors have demonstrated efficacy in animal models of epil epsy, cerebral ischaemia as well as pain and inflammation, thus suggesting their potential therapeutic utility for these conditions.