The 1,2,4-Triazolo[4,3‑a]pyrazin-3-one
as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor
Antagonists. Structural Investigations to Target the A2A Receptor Subtype
posted on 2017-06-07, 00:00authored byMatteo Falsini, Lucia Squarcialupi, Daniela Catarzi, Flavia Varano, Marco Betti, Diego Dal Ben, Gabriella Marucci, Michela Buccioni, Rosaria Volpini, Teresa De Vita, Andrea Cavalli, Vittoria Colotta
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 hA2A adenosine receptor (AR). Several
compounds possessed nanomolar affinity for the hA2A AR
(Ki = 2.9–10 nM) and some, very
interestingly, also showed high selectivity for the target. One selected
potent hA2A 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.