Selective adenosine A(2A) receptor antagonists

In the early 1990s it became clear that the A(2A) adenosine receptor had characteristics that made it distinct from the other A(1), A(2B) and A(3) adenosine receptors. Great progress has been made with the discovery of selective A(2A) receptor antagonists. A variety of synthetic substitutions on the xanthine moiety led the chemists of Kyowa-Hakko to discover that introduction of the styryl group in the 8 position of xanthines was critical in achieving compounds endowed with selective A(2A) receptor antagonistic properties. One compound, KW 6002, (E)1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine, is currently being developed for treatment of Parkinson's disease. A number of non-xanthine heterocycles have also been synthesized starting from the non-selective adenosine antagonist CGS 15943, a triazoloquinazoline. Thus, replacement of the phenyl ring of CGS 15943 with a heterocyclic ring such as pyrazole or imidazole, led to a series of interesting compounds whose prototype, SCH 58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, has become a reference A(2A) receptor. antagonist. Modification of N7 substituents has progressed to optimize A(2A) receptor selectivity and pharmacokinetic characteristics. A related class of compounds having a bicyclic instead of the tricyclic ring structure is also of interest. The prototype of these triazintriazolo derivatives, ZM 241385, is a potent A(2A) receptor antagonist; however, it also shows interactions with A(2B) receptors. The relevance of the A(2A) receptors in specific disease states, especially in the central nervous system, makes this class of adenosine receptor blockers of interest for treatment of neurodegenerative disorders such as ParkiDson's disease. (C) 2001 Elsevier Science S.A. All rights reserved.