Piperazine Derivatives of [1,2,4]Triazolo[1,5-a][1,3,5]triazine as Potent and Selective Adenosine A<INF>2</INF><INF>a</INF> Receptor Antagonists

The [1,2,4]triazolo[1,5-a]triazine derivative <BO>3</BO>, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A<INF>2a</INF> receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5-a]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A<INF>2a</INF> binding affinity of some of the best piperazine derivatives is almost as good as that of compound <BO>3</BO>. The selectivity level over the adenosine A<INF>1</INF> receptor subtype for some of the more active analogues is also fairly high, >400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5-a]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound <BO>35</BO>). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5-a]triazine also possessed good oral efficacy in rodent models of Parkinson's disease. For instance, compound <BO>34</BO> was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.