Design and development of 1,3,5-triazine-thiadiazole hybrids as potent adenosine A2A receptor (A2AR) antagonist for benefit in Parkinson's disease

Abstract

Various studies showed adenosine A₂A receptors (A₂ARs) antagonists have profound therapeutic efficacy in Parkinsons Disease (PD) by improving dopamine transmission, thus being active in reversing motor deficits and extrapyramidal symptoms related to the disease. Therefore, in the presents study, we have showed the development of novel 1,3,5-triazine-thiadiazole derivative as potent A₂ARs antagonist. In the radioligand binding assay, these molecules showed excellent binding affinity with A₂AR compared to A₁R, with significant selectivity. Results suggest, compound 7e as most potent antagonist of A₂AR among the tested series. In docking analysis with A₂AR protein model, compound 7e found to be deeply buried into the cavity of receptor lined via making numerous interatomic contacts with His264, Tyr271, His278, Glu169, Ala63, Val84, Ile274, Met270, Phe169. Collectively, our study demonstrated 1,3,5-triazine-thiadiazole hybrid as a highly effective scaffold for the design of new A₂A antagonists.

Keywords: 1,3,5-triazine; Adenosine A(2)A receptor; Antagonist; Docking; Parkinson’s disease.