Novel Bicyclic Piperazine Derivatives of Triazolotriazine and Triazolopyrimidines as Highly Potent and Selective Adenosine A<INF>2</INF><INF>A</INF> Receptor Antagonists

A series of bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines was synthesized. Some of these analogues show high affinity and excellent selectivity for adenosine A<INF>2a</INF> receptor versus the adenosine A<INF>1</INF> receptor. Structure−activity-relationship (SAR) studies based on octahydropyrrolo[1,2-a]pyrazine and octahydropyrido[1,2-a]pyrazine with various capping groups are reported. Among these analogues, the most potent and selective A<INF>2a</INF> antagonist <BO>26h </BO>has a K<INF>i</INF> value of 0.2 nM and is 16 500-fold selective with respect to the A<INF>1</INF> receptor. Among a number of compounds tested, compounds <BO>21a</BO> and <BO>21c</BO> exhibited significantly improved metabolic stability. Compounds <BO>21a</BO>, <BO>21c</BO>, and <BO>18a</BO> showed good oral efficacy in rodent catalepsy models of Parkinson's disease.