Discovery of Novel and Selective Adenosine A_2A Receptor Antagonists for Treating Parkinson's Disease through...

Among non-dopaminergic strategies for combating Parkinson's disease (PD), antagonism of the A_2A adenosine receptor (AR) has emerged to show great potential. In this study, on the basis of two crystal structures of the A_2A AR with the best capability to distinguish known antagonists from decoys, docking-based virtual screening (VS) was conducted to identify novel A_2A AR antagonists. A total of 63 structurally diverse compounds identified by VS were submitted to experimental testing, and 11 of them exhibited substantial activity against the A_2A AR (K_i < 10 μM), including two compounds with K_i below 1 μM (compound 43, 0.42 μM; compound 51, 0.27 μM) and good A_2A/A₁ selectivity (fold < 0.1). Compounds 43 and 51 demonstrated antagonistic activity according to the results of cAMP measurements (cAMP IC₅₀ = 1.67 and 1.80 μM, respectively) and showed good efficacy in the haloperidol-induced catalepsy (HIC) rat model for PD at doses of up to 30 mg/kg. Further lead optimization based on a substructure searching strategy led to the discovery of compound 84 as an excellent A_2A AR antagonist (A_2A K_i = 54 nM, A_2A/A₁ fold < 0.1, cAMP IC₅₀ = 0.3 μM) that exhibited significant improvement in anti-PD efficacy in the HIC rat model.