Potent, Selective, and Orally Active Adenosine A_2A Receptor Antagonists: Arylpiperazine Derivatives of Pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidines.

Abstract

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines. -Optimization of the lead structure (Id) results in the identification of ether (If), which shows broad selectivity, good pharmacokinetic properties and excellent in vivo activity. -(NEUSTADT*, B. R.; et al.; Bioorg. Med.

The effects of adenosine A2A receptor antagonists on haloperidol-induced movement disorders in primates

“…To that end, we found that SCH 412348, KW-6002, and caffeine could delay or prevent the onset of EPS as demonstrated by a reduction in the mean EPS score across the colony of monkeys. Given that SCH 412348 and KW-6002 are highly selective for the A 2A receptor (Shimada et al 1997;Neustadt et al 2007), it seems highly likely that the ability of these compounds to attenuate haloperidolinduced EPS is mediated via the A 2A receptor subtype. Since the selective A 1 receptor antagonist, DCPCX, was relatively ineffective in blocking haloperidol-induced EPS, it is also likely that caffeine's efficacy in this model is due to its ability to antagonize the A 2A receptor.…”

“…The principal aim of these studies was to test this hypothesis using primate models of antipsychotic-induced EPS and catalepsy. While we and other investigators have examined the effects of adenosine receptor antagonists on drug-induced EPS and catalepsy in rodents (Kanda et al 1994;Kafka and Corbett 1996;Malec 1997;Correa et al 2004;Neustadt et al 2007;Pinna et al 2007), there is no such work in primates. To this end, the A 2A receptor antagonists, SCH 412348 (A 2A Ki=0.6 nM, A 1 Ki≥960 nM; Neustadt et al 2007) and KW-6002 (A 2A Ki=2.2 nM, A 1 Ki=150 nM; Shimada et al 1997); the nonselective adenosine receptor antagonist, caffeine; and the A 1 receptor antagonist, DPCPX (Lohse et al 1987) were tested in two established primate models; haloperidol-induced EPS in Cebus apella monkeys (Gunne and Barany 1976;Weiss et al 1977) and…”

Purinergic signaling in Parkinson's disease. Relevance for treatment

“…By contrast, istradefylline was approved for use in Japan for treatment of PD as an enhancer of L-DOPA actions, especially of the wearing-off phenomena [72], with the trade name Nouriast® (20 mg tablets). [73,74]. Also this compound reduced wearing-off time by about 1h [70], but again phase III clinical trials did not show substantial benefits over L-DOPA either in monotherapy or in combined therapy with L-DOPA.…”

A2A Receptor Ligands: Past, Present and Future Trends

“…(7)) with substituted phenylpiperazinethyl groups [153]. In particular one of these compounds SCH 420814 (84, Fig.…”

“…However, among the tricyclic compounds, the pyrazolotriazolo-pyrimidine derivatives were considered the most promising A 2A AR ligands [16,17,[153][154][155][156]]. An extensive SAR study performed on these types of derivatives permitted the determination of important requirements for A 2A AR affinity and selectivity, such as the presence of a free amino group at the 5-position of the furan ring, and the substitution of the pyrazole ring.…”