Preladenant

Preladenant is a potent competitive antagonist of the human A_2A receptor (K_i=1.1 nM) and has >1000-fold selectivity over all other adenosine receptors. IC50 & Target: Ki: 1.1 nM (Adenosine A_2A receptor)^[1] In Vitro: Preladenant also completely antagonizes cAMP in cells expressing the recombinant human A_2A receptor. Preladenant is determined to has K_B values of 1.3 nM at the A_2A receptor; the value is in good agreement with the K_i value determined in the radioligand binding assay. A similar functional assay with A_2B receptor-expressing cells is used to demonstrate selectivity over A_2B receptors. In this assay, the K_B value for Preladenant is 1.2 μM, indicating that Preladenant is 923-fold selective for the A_2A receptor over the A_2B receptor^[1]. In Vivo: Preladenant (1 mg/kg) inhibits L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Preladenant exhibits antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test^[1]. Preladenant produces a dose-dependent reduction in parkinsonian scores at doses of 1 mg/kg (min score: 9.0) and 3 mg/kg (min score: 6.5). A subthreshold dose of Preladenant reduces minimum and mean parkinsonian scores in animals treated with 3 mg kg of L-Dopa to 5.25 and 6.88 respectively. A Wilcoxin test is used to compare individual treatments against vehicle. Preladenant (3 mg/kg), L-Dopa (3, 6, and 12 mg/kg), and the combination of Preladenant and L-Dopa (1 or 3 mg/kg+3 mg/kg) are all significantly improved on the minimum parkinsonian score. In addition, both the 12 mg/kg L-Dopa and L-Dopa+Preladenant groups are significantly improved on both minimum and mean parkinsonian scores relative to the 3 mg/kg L-Dopa group^[2].