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

Autor: Jones PG; Discovery and Preclinical Research, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA. Electronic address: philip.jones@sunovion.com., Hewitt MC; Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, USA., Campbell JE; Epizyme Inc., 400 Technology Square 4th Floor, Cambridge, MA 02139, USA., Quinton MS; Retrophin Inc., 301 Binney St. 3rd floor, Cambridge, MA 02142, USA., Engel S; Discovery and Preclinical Research, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA., Lew R; Translational Medicine and Early Development, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA., Campbell U; Translational Medicine and Early Development, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA., Burdi DF; Discovery and Preclinical Research, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA.
Jazyk: angličtina
Zdroj: Pharmacology, biochemistry, and behavior [Pharmacol Biochem Behav] 2015 Aug; Vol. 135, pp. 46-52. Date of Electronic Publication: 2015 May 16.
DOI: 10.1016/j.pbb.2015.04.017
Abstrakt: In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7mg/kg (p.o.), corresponding to plasma and brain exposures of 28ng/mL and 43ng/g, respectively. Using microdialysis, we show that 3mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3mg/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 10mg/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 0.3mg/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.
(Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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