Adenosine kinase inhibitors as a novel approach to anticonvulsant therapy

Adenosine levels increase at seizure foci as part of a postulated endogenou s negative feedback mechanism that controls seizure activity through activa tion of A(1) adenosine receptors. Agents that amplify this site- and event- specific surge of adenosine could provide antiseizure activity similar to t hat of adenosine receptor agonists but with fewer dose-limiting side effect s. inhibitors of adenosine kinase (AK) were examined because AK is normally the primary route of adenosine metabolism. The AK inhibitors 5'-amino-5'-d eoxyadenosine, 5-iodotubercidin, and 5'-deoxy-5-iodotubercidin inhibited ma ximal electroshock (MES) seizures in rats. Several structural classes of no vel AK inhibitors were identified and shown to exhibit similar activity, in cluding a prototype inhibitor, 4-(N-phenylamino)- 5-phenyl-7-(5'-deoxyribof uranosyl)pyrrolo[2,3-d]pyrimidine (GP683; MES ED50 = 1.1 mg/kg). AK inhibit ors also reduced epileptiform discharges induced by removal of Mg2+ in a ra t neocortical preparation. Overall, inhibitors of adenosine deaminase or of adenosine transport were less effective. The antiseizure activities of GP6 83 in the in vivo and in vitro preparations were reversed by the adenosine receptor antagonists theophylline and 8-(p-sulfophenyl)theophylline. GP683 showed little or no hypotension or bradycardia and minimal hypothermic effe ct at anticonvulsant doses. This improved side effect profile contrasts mar kedly with the profound hypotension, bradycardia, and hypothermia and great er inhibition of motor function observed with the adenosine receptor agonis t N-6-cyclopentyladenosine acid opens the way to clinical evaluation of AK inhibitors as a novel, adenosine-based approach to anticonvulsant therapy.