Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing.

Autor:	Modi ME; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Majchrzak MJ; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Fonseca KR; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Doran A; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Osgood S; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Vanase-Frawley M; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Feyfant E; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., McInnes H; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Darvari R; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Buhl DL; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.)., Kablaoui NM; Neuroscience and Pain Research Unit (M.E.M., M.J.M., D.L.B.), Department of Pharmacokinetics, Dynamics and Metabolism (K.R.F.), Global Biotherapeutics Technologies (E.F.), and Worldwide Medicinal Chemistry (N.M.K.), Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts; Department of Pharmacokinetics, Dynamics and Metabolism, Worldwide Research and Development, Pfizer Inc., Groton, Connecticut (A.D., S.O., M.V.-F.); and Biotherapuetics Pharmaceutical Research and Development, Worldwide Research and Development, Pfizer Inc., Andover, Massachusetts (H.M., R.D.) Natasha.M.Kablaoui@pfizer.com.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2016 Aug; Vol. 358 (2), pp. 164-72. Date of Electronic Publication: 2016 May 23.
DOI:	10.1124/jpet.116.232702
Abstrakt:	Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non-brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response. (Copyright © 2016 The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu