Adenosine A2AR/A1R Antagonists Enabling Additional H3R Antagonism for the Treatment of Parkinson's Disease

Abstract

Adenosine A₁/A_2A receptors (A₁R/A_2AR) represent targets in nondopaminergic treatment of motor disorders such as Parkinson's disease (PD). As an innovative strategy, multitargeting ligands (MTLs) were developed to achieve comprehensive PD therapies simultaneously addressing comorbid symptoms such as sleep disruption. Recognizing the wake-promoting capacity of histamine H₃ receptor (H₃R) antagonists in combination with the "caffeine-like effects" of A₁R/A_2AR antagonists, we designed A₁R/A_2AR/H₃R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H₃R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H₃R affinities (K_i < 55 nM). Compound 4 (ST-2001, K_i (A₁R) = 11.5 nM, K_i (A_2AR) = 7.25 nM) and 12 (ST-1992, K_i (A₁R) = 11.2 nM, K_i (A_2AR) = 4.01 nM) were evaluated in vivo. l-DOPA-induced dyskinesia was improved after administration of compound 4 (1 mg kg^-1, i.p. rats). Compound 12 (2 mg kg^-1, p.o. mice) increased wakefulness representing novel pharmacological tools for PD therapy.