Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition

摘要: Abstract In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is potent (1.0 nM) inhibitor human in vitro , with good selectivity (> 16000-fold) against other PDEs. an vivo occupancy RO 50 value was determined to be 0.7 mg/kg (p.o.), corresponding plasma and brain exposures 28 ng/mL 43 ng/g, respectively. Using microdialysis, show that 3 mg/kg (p.o.) significantly increased rat striatal cGMP concentrations. Furthermore, inhibits PCP-induced hyperlocomotion at doses 1 59–86% occupancy. At similar catalepsy time on bar but maximal effect less than seen haloperidol. EEG 3 10 mg/kg suppressed REM intensity latency sleep. We also demonstrate procognitive object recognition assay. These appear require inhibition reversal or effects, as improvements index were 0.3 mg/kg above. Our data potent, orally active therapeutic potential number psychiatric indications.