More and more evidence suggesting that the adenosine A2A receptor is a promising target for antiparkinson treatment. Adenosine A2A receptors always locate within the caudate-putamen, nucleus accumbens, and olfactory tubercle. The concentration within the basal ganglia means a specific functional role for these receptors in neuronal communication. Especially, it plays an important role in motor behavior.

What’s more, the ability of adenosine A2A receptor antagonists to modulate basal ganglia neurotransmission has been proven in Parkinson’s disease (PD) model. For example, ST1535, is a potent adenosine A2A antagonist. It improves animal performance in a number of experimental models of PD. Furthermore, ST1535 potentiates contralateral turning behavior induced by L-DOPA in 6-OHDA-lesioned rats. It also reduces haloperidol-elicited catalezpsy.There exists a functional antagonism between A2A adenosine receptors and D2 dopamine receptors.
Acute activation of D2 dopamine receptors can suppress cyclic AMP accumulation. However, activation of A2A adenosine receptors stimulates its accumulation.
Evaluation of the in vivo metabolic fate of ST1535 in rat and monkey plasma, including ST3932 (M2) and ST4206 (M3).

ST4206 is a potent and orally active adenosine A2A antagonist.

ST4206 inhibits agonist-induced cAMP accumulation with an IC50 of 990 nM. And the IC50 values on cyclic AMP were 427 nM and 450 nM, respectively. Additionally, the Kis are 12 nM and 197 nM for adenosine A2A receptor and adenosine A1 receptor, respectively.
ST4206 is orally active at concentrations of 10, 20, and 40 mg/kg in haloperidol-induced catalepsy in mice. And ST4206 antagonizes haloperidol-induced catalepsy, and increases motor activity in a dose-dependent manner. At dosages of 20 and 40 mg/kg, ST4206 significantly increases the number of contralateral turns induced by l-DOPA in rats.
The metabolite of ST1535, ST4206, shows a pharmacological activity similar to ST1535 both in vitro and in vivo. It may act as a potential pharmacological alternative to ST1535

In conclusion, from a behavioral point of view, ST4206 is similarly effective as ST1535. The metabolite exhibits the same characteristics as the parent drug ST1535. Therefore, ST4206 has the potential for PD research.


[1]. Stasi MA, et al. Eur J Pharmacol. 2015 Aug 15;761:353-61.