| Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. | |
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MedLine Citation:
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PMID: 18287214 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function. |
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Authors:
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C J Schmidt; D S Chapin; J Cianfrogna; M L Corman; M Hajos; J F Harms; W E Hoffman; L A Lebel; S A McCarthy; F R Nelson; C Proulx-LaFrance; M J Majchrzak; A D Ramirez; K Schmidt; P A Seymour; J A Siuciak; F D Tingley; R D Williams; P R Verhoest; F S Menniti |
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Publication Detail:
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Type: Journal Article Date: 2008-02-20 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 325 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-04-18 Completed Date: 2008-05-19 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 681-90 Citation Subset: IM |
Affiliation:
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Neuroscience, Pfizer Global Research and Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA. Christopher.j.schmidt@pfizer.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Behavior, Animal / drug effects Brain / drug effects, metabolism Cyclic AMP / metabolism Cyclic GMP / metabolism Dopamine / metabolism Male Mice Mice, Inbred C57BL Motor Activity / drug effects Phosphodiesterase Inhibitors / blood, pharmacokinetics, pharmacology* Phosphoric Diester Hydrolases / genetics, physiology* Pyrazoles / pharmacology* Quinolines / pharmacology* Rats Rats, Inbred F344 Recombinant Proteins / antagonists & inhibitors, genetics Schizophrenia / drug therapy*, metabolism, physiopathology Startle Reaction / drug effects |
| Chemical | |
Reg. No./Substance:
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0/2-(4-(pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)phenoxymethyl)quinoline succinic acid; 0/Phosphodiesterase Inhibitors; 0/Pyrazoles; 0/Quinolines; 0/Recombinant Proteins; 60-92-4/Cyclic AMP; 7665-99-8/Cyclic GMP; EC 3.1.4.-/PDE10A protein, rat; EC 3.1.4.-/Pde10a protein, mouse; EC 3.1.4.-/Phosphoric Diester Hydrolases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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