Therapeutic potential of adenosine kinase inhibitors

Abstract

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