A2A-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand

Abstract

A2A adenosine receptor (AR) antagonists are promising new drugs for the treatment of Parkinson's disease. Further potential therapeutic indications for A2A AR antagonists include dementias, ischemias, and pain. Potent, selective A2A AR antagonists have been developed, but their generally low water solubility is a major problem for conducting in vivo experiments. We developed a water-soluble phosphate prodrug (MSX-3) of a potent, selective A2A AR antagonist (MSX-2), which is stable in aqueous solution, but rapidly cleaved in vivo by phosphatases to release the active compound MSX-2. Intracerebral application of MSX-3 led to a stimulation of motor activity in rats. Catalepsy, induced by pretreatment with either dopamine D1 or D2 antagonist, was potently reversed by intracerebral application of MSX-3. A new A2A-selective antagonist radioligand, [3H]MSX-2, was prepared, which exhibits a KD value of 8 Nm at rat brain striatal membranes. Drug Dev. Res. 45:190–197, 1998. © 1998 Wiley-Liss, Inc.