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

Adenosine A 1 /A 2A receptors (A 1 R/A 2A R) 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 H 3 receptor (H 3 R) antagonists in combination with the “caffeine-like effects” of A 1 R/A 2A R antagonists, we designed A 1 R/A 2A R/H 3 R MTLs, where a piperidino-/pyrrolidino(propyloxy)phenyl H 3 R pharmacophore was introduced with overlap into an adenosine antagonist arylindenopyrimidine core. These MTLs showed distinct receptor binding profiles with overall nanomolar H 3 R affinities ( K i < 55 nM). Compound 4 ( ST-2001, K i (A 1 R) = 11.5 nM, K i (A 2A R) = 7.25 nM) and 12 ( ST-1992, K i (A 1 R) = 11.2 nM, K i (A 2A R) = 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.