Discovery of Novel and Selective Adenosine A 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 adenosine receptor (AR) has emerged to show great potential. In this study, on the basis of two crystal structures of the A AR with the best capability to distinguish known antagonists from decoys, docking-based virtual screening (VS) was conducted to identify novel A 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 AR (K < 10 μM), including two compounds with K below 1 μM (compound 43, 0.42 μM; compound 51, 0.27 μM) and good A/A selectivity (fold < 0.1). Compounds 43 and 51 demonstrated antagonistic activity according to the results of cAMP measurements (cAMP IC = 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 AR antagonist (A K = 54 nM, A/A fold < 0.1, cAMP IC = 0.3 μM) that exhibited significant improvement in anti-PD efficacy in the HIC rat model.