The 1,2,4-Triazolo[4,3-<i>a</i>]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A_2AReceptor Subtype

Abstract

In this work, we describe the identification of the 1,2,4-triazolo[4,3-a]pyrazin-3-one as a new versatile scaffold for the development of adenosine human (h) receptor antagonists. The new chemotype ensued from a molecular simplification approach applied to our previously reported 1,2,4-triazolo[4,3-a]quinoxalin-1-one series. Hence, a set of novel 8-amino-2-aryl-1,2,4-triazolopyrazin-3-one derivatives, featured by different substituents on the 2-phenyl ring (R) and at position 6 (R₆), was synthesized with the main purpose of targeting the hA_2A adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA_2A AR (K_i = 2.9-10 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA_2A AR antagonist (12, R = H, R₆ = 4-methoxyphenyl) demonstrated some ability to counteract MPP⁺-induced neurotoxicity in cultured human neuroblastoma SH-SY5Y cells, a widely used in vitro Parkinson's disease model. Docking studies at hAR structures were performed to rationalize the observed affinity data.