NDLI: Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats

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Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats

Content Provider	Springer Nature Link
Author	Snyder, Gretchen L. Prickaerts, Jos Wadenberg, Marie Louise Zhang, Lei Zheng, Hailin Yao, Wei Akkerman, Sven Zhu, Hongwen Hendrick, Joseph P. Vaver, Kimberly E. Davis, Robert Li, Peng Mates, Sharon Wengle, Lawrence P.
Copyright Year	2016
Abstract	Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed.The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1).ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences). Effects of ITI-214 (0.1–10 mg/kg, po) on memory performance were assayed in rats using the novel object recognition (NOR) paradigm, with drug given at specified time points prior to or following exposure to objects in an open field. ITI-214 was evaluated for potential drug-drug interaction with risperidone in rats using conditioned avoidance response (CAR) and pharmacokinetic assessments.ITI-214 inhibited PDE1A (K i = 33 pmol) with >1000-fold selectivity for the nearest other PDE family (PDE4D) and displayed minimal off-target binding interactions in a 70-substrate selectivity profile. By using specific timing of oral ITI-214 administration, it was demonstrated in the NOR that ITI-214 is able to enhance acquisition, consolidation, and retrieval memory processes. All memory effects were in the absence of effects on exploratory behavior. ITI-214 did not disrupt the risperidone pharmacokinetic profile or effects in CAR.ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1–10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress.
Starting Page	3113
Ending Page	3124
Page Count	12
File Format	PDF
ISSN	00333158
Journal	Psychopharmacology
Volume Number	233
Issue Number	17
e-ISSN	14322072
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2016-06-24
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Novel object recognition Phosphodiesterase-1 Cyclic GMP Cyclic AMP Memory Conditioned avoidance response Neurosciences Pharmacology/Toxicology Psychiatry
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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