A(2A)-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand

A(2A) adenosine receptor (AR) antagonists are promising new drugs for the t reatment of Parkinson's disease. Further potential therapeutic indications for A(2A) AR antagonists include dementias, ischemias, and pain. Potent, se lective A(2A) AR antagonists have been developed, but their generally low w ater solubility is a major problem for conducting in vivo experiments. We d eveloped a water-soluble phosphate prodrug (MSX-3) of a potent, selective A (2A) AR antagonist (MSX-2), which is stable in aqueous solution, but rapidl y cleaved in vivo by phosphatases to release the active compound MSX-2. Int racerebral application of MSX-3 led to a stimulation of motor activity in r ats. Catalepsy, induced by pretreatment with either dopamine D1 or D2 antag onist, was potently reversed by intracerebral application of MSX-3. A new A (2A)-selective antagonist radioligand, [H-3]MSX-2, was prepared, which exhi bits a K-D value of 8 nM at rat brain striatal membranes. Drug Dev. Res, 45 :130-197, 1998. (C) 1998 Wiley-Liss, Inc.