Selective adenosine A 2A receptor antagonists

Abstract

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 Parkinson's disease.