IN274489: Thiazolo[4,3-e] 1,2,4-triazolo [1,5-c] pyrimidine and thiazolo [4,3-e] 1,3-imidazo [1,2-c] pyrimidine derivatives as adenosine A2A receptor antagonists

Novel thiazolotriazolopyrimidine (25-36) and thiazoloimidazolo pyrimidine (39-44) designed as potential adenosine A2A receptor (A2AR) antagonists were synthesized. Molecular docking studies revealed that all compounds (25-36) and (39-44) exhibited strong interaction with A2AR. The strong interaction of the compounds (23-33) with A2AR in silico was confirmed by their high binding affinity with human A2AR stably expressed in HEK293 cells using radioligand binding assay. The compounds 25-36 demonstrated substantial binding affinity and selectivity for A2AR as compared to SCH58261, a standard A2AR antagonist. A decline in A2AR-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A2AR antagonist potential of the compounds 25-36. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 25-36 further support their role in the alleviation of PD symptoms.