In:
Pharmacology Research & Perspectives, Wiley, Vol. 4, No. 4 ( 2016-08)
Abstract:
Recently, we identified a novel phosphodiesterase 10A ( PDE 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). PDM ‐042 showed potent inhibitory activities for human and rat PDE 10A with IC 50 values of less than 1 nmol/L and more than 1000‐fold selectivity against other phosphodiesterases. Tritiated PDM ‐042, [ 3 H] 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 [ 3 H] PDM ‐042 was displaced in a concentration‐dependent manner by PDM ‐042 and another structurally unrelated PDE 10A 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 PDE 10A 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 PDE 10A and may have therapeutic potential for the treatment of schizophrenia.
Type of Medium:
Online Resource
ISSN:
2052-1707
,
2052-1707
Language:
English
Publisher:
Wiley
Publication Date:
2016
detail.hit.zdb_id:
2740389-0
SSG:
15,3
Permalink