Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8350445 | Pharmacology Biochemistry and Behavior | 2015 | 7 Pages |
Abstract
In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0Â nM) inhibitor of human PDE10A in vitro, with good selectivity (>Â 16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7Â mg/kg (p.o.), corresponding to plasma and brain exposures of 28Â ng/mL and 43Â ng/g, respectively. Using microdialysis, we show that 3Â mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3Â mg/kg (p.o.) corresponding to 59-86% occupancy. At similar doses in a catalepsy study, the time on the bar was increased but the maximal effect was less than that seen with haloperidol. In an EEG study, 3 and 10Â mg/kg (p.o.) SEP-39 suppressed REM intensity and increased the latency to REM sleep. We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3Â mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications.
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Authors
Philip G. Jones, Michael C. Hewitt, John E. Campbell, Maria S. Quinton, Sharon Engel, Robert Lew, Una Campbell, Douglas F. Burdi,