Discovery of Novel and Selective Adenosine A2A Receptor Antagonists for Treating Parkinson's Disease through Comparative Structure-Based Virtual Screening

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 mu M), including two compounds with Ki below 1 mu M (compound 43, 0.42 mu M; compound 51, 0.27 mu M) and good A(2A)/A(1), 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 yM, 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) = 54 nM, A(2A)/A(1) fold < 0.1, cAMP IC50 = 0.3 mu M) that exhibited significant improvement in anti-PD efficacy in the HIC rat model.