In Vivo Characterization of a Dual Adenosine A_2A/A₁ Receptor Antagonist in Animal Models of Parkinson’s Disease

Abstract

The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.

Unprecedented therapeutic potential with a combination of A2A/NR2B receptor antagonists as observed in the 6-OHDA lesioned rat model of Parkinson's disease

“…A 2A and NR2B receptor antagonists both show anti-parkinsonian activity in preclinical models; however, the effects are weaker in magnitude compared with dopamine agonists or L-Dopa [14][15][16]34]. A 2A antagonists have also demonstrated weak efficacy in clinical trials when tested as monotherapy in PD patients [22].…”

“…A 2A antagonists have been shown to be efficacious against haloperidolinduced catalepsy [16,20,50] and showed positive effects in the forepaw stepping test in unilaterally 6-OHDA lesioned rats [51] and in the rotarod test [52]. However, most studies failed to demonstrate a significant effect of A 2A receptor antagonists on the level of contralateral rotation in lesioned rats in the absence of L-Dopa [14][15][16]53]. To our knowledge, this is the first time that the efficacy of A 2A receptor antagonists on motor activity has been systematically evaluated in unilaterally 6-OHDA-lesioned rats by measuring the general level of motor activity.…”

“…In rodent or primate models, when A 2A antagonists are given alone (i.e. as monotherapy) to severely DA-depleted animals they show only marginal activity [14][15][16], however, they are able to significantly potentiate dopaminergic treatment [17][18][19][20][21]. In the clinic, when the A 2A antagonist Istradefylline was given as monotherapy (i.e.…”

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease

“…This assay involves antagonizing D 2 receptors in medium striatal spiny neurons of the indirect pathway and it has been used to assess the potential symptomatic efficacy of novel non-dopaminergic agents in PD, including mGlu 4 -positive allosteric modulators, adenosine A 2A /A 1 antagonists and mGlu 7 agonists (Greco et al, 2010;Neustadt et al, 2009;Niswender et al, 2008;Shook et al, 2010). The blockade of D 2 receptors by haloperidol (1 mg/kg) results in rigidity and catalepsy in rodents that mimics a key symptom of PD, namely the difficulty of patients to initiate movement.…”

Adenosine A2A Receptor Antagonists as Drugs for Symptomatic Control of Parkinson’s Disease in Preclinical Studies

“…7.2) (Drabczyńska et al 2011;Gillespie et al 2009;Hodgson et al 2009;Jones et al 2013;Kanda et al 1994;Mandhane et al 1997;Pinna et al 2005;Shiozaki et al 1999;Shook et al 2010Shook et al , 2013Stasi et al 2006;Villanueva-Toledo 2003;Wardas et al 2003;Weiss et al 2003). Furthermore, the co-administration of several A.…”