Pharmacological characterization of a novel potent, selective, and orally active phosphodiesterase 10A inhibitor, PDM-042 [(E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine] in rats: potential for the treatment of schizophrenia.

ABSTRACT: Recently, we identified a novel phosphodiesterase 10A (PDE10A) inhibitor, PDM-042 ((E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine). PDM-042 showed potent inhibitory activities for human and rat PDE10A with IC ₅₀ values of less than 1 nmol/L and more than 1000-fold selectivity against other phosphodiesterases. Tritiated PDM-042, [³H]PDM-042, had high affinity for membranes prepared from rat striatum with a K_d value of 8.5 nmol/L. The specific binding of [³H]PDM-042 was displaced in a concentration-dependent manner by PDM-042 and another structurally unrelated PDE10A inhibitor, MP-10. In rat studies, PDM-042 showed excellent brain penetration (striatum/plasma rat

SUBMITTER: Arakawa K 

PROVIDER: S-EPMC5242175 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature