Recent developments in the discovery of novel adenosine kinase inhibitors: Mechanism of action and therapeutic potential

Adenosine (ADO) is an endogenous inhibitory neuromodulator that limits cellular excitability in response to tissue trauma and inflammation. Adenosine kinase (AK; EC 2.7.1.20) is the primary metabolic enzyme regulating intra- and extracellular concentrations of ADO. AK inhibitors have been shown to significantly increase ADO concentrations at sites of tissue injury and to provide effective antinociceptive, anti inflammatory, and anticonvulsant activity in animal models. Structurally novel nucleoside and nonnucleoside AK inhibitors that demonstrate high specificity for the AK enzyme compared with other ADO metabolic enzymes, transporters, and receptors have recently been synthesized, These compounds have also demonstrated improved cellular and tissue penetration compared with earlier tubercidin analogs. These compounds have been shown to exert beneficial effects in animal models of pain, inflammation and epilepsy with reduced cardiovascular side effects compared with direct acting ADO receptor (P1) agonists, thus supporting the hypothesis that AK inhibitors can enhance the actions of ADO in a site and event-specific fashion.