(3 S )-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent.

Autor:	Hjorth S; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.) clas.sonesson@irlab.se stephan.hjorth@irlab.se., Waters S; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Waters N; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Tedroff J; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Svensson P; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Fagerberg A; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Edling M; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Svanberg B; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Ljung E; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Gunnergren J; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., McLean SL; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Grayson B; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Idris NF; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Neill JC; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.)., Sonesson C; Integrative Research Laboratories Sweden AB (IRL AB), Gothenburg, Sweden (S.H., S.W., N.W., J.T., P.S., A.F., M.E., B.S., E.L., J.G., C.S.); Pharmacilitator AB, Vallda, Sweden (S.H.); Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden (S.H.); School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West Yorkshire, United Kingdom (S.L.M.); and Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Medicine, Biology and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom (B.G., N.F.I., J.C.N.) clas.sonesson@irlab.se stephan.hjorth@irlab.se.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2020 Sep; Vol. 374 (3), pp. 404-419. Date of Electronic Publication: 2020 Jun 30.
DOI:	10.1124/jpet.120.000037
Abstrakt:	Here we describe for the first time the distinctive pharmacological profile for (3 S )-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and α 2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT: This report describes the distinctive preclinical profile of (3 S )-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. (Copyright © 2020 The Author(s).)
Databáze:	MEDLINE
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