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 ratio = 6.3), occupancy rate (86.6% at a dose of 3 mg/kg), and good oral bioavailability (33%). These data indicate that PDM‐042 is a potent, selective, orally active, and brain‐penetrable PDE10A inhibitor. In behavioral studies using rat models relevant to schizophrenia, PDM‐042 significantly antagonized MK‐801‐induced hyperlocomotion (0.1–0.3 mg/kg) without affecting spontaneous locomotor activity and attenuated the conditioned avoidance response (CAR) (0.3–1 mg/kg). In tests for adverse effects, PDM‐042 had a minimal effect on catalepsy, even at a much higher dose (10 mg/kg) than the minimal effective dose (0.3 mg/kg) in the CAR. Furthermore, PDM‐042 had no effect on prolactin release or glucose elevation up to 3 mg/kg, while risperidone increased prolactin release and olanzapine enhanced glucose levels at doses near their efficacious ones in the CAR. Our results suggest that PDM‐042 is a good pharmacological tool that can be used to investigate the role of PDE10A and may have therapeutic potential for the treatment of schizophrenia.