sch412348

Description: SCH 412348 is a novel and potent competitive antagonists of the human A(2A) receptor (K(i) = 1.1 and 0.6 nM, respectively) and has > 1000-fold selectivity over all other adenosine receptors, making it the most selective A(2A) receptor antagonist reported to date. SCH 412348 attenuates hypolocomotion induced by the A(2A) receptor agonist CGS-21680 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine, suggesting that it inhibits A(2A) receptor activity in vivo. Its high degree of selectivity and robust in vivo activity make SCH 412348 useful tools to investigate the role of the A(2A) receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3, 4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A(2A) receptor antagonists and provide further evidence of the potential therapeutic benefits of A(2A) receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD).

References: J Pharmacol Exp Ther. 2009 Jul; 330(1):294-303.