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Journal of Pharmacology and Experimental Therapeutics

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OtherDrug Discovery and Translational Medicine

(3S)‐3‐(2,3‐difluorophenyl)‐3‐methoxypyrrolidine (IRL752) - a novel cortical-preferring catecholamine transmission- and cognition-promoting agent

Stephan Hjorth, Susanna Waters, Nicholas Waters, Joakim Tedroff, Peder Svensson, Anne Fagerberg, Malin Edling, Boel Svanberg, Elisabeth Ljung, Jenny Gunnergren, Samantha L McLean, Ben Grayson, Nagi F Idris, Joanna C Neill and Clas Sonesson
Journal of Pharmacology and Experimental Therapeutics June 30, 2020, JPET-AR-2020-000037; DOI: https://doi.org/10.1124/jpet.120.000037
Stephan Hjorth
1Integrative Research Laboratories AB, Sweden
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  • For correspondence: stephan.hjorth@telia.com
Susanna Waters
2Integrative Research Laboratories Sweden AB, Sweden
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  • ORCID record for Susanna Waters
Nicholas Waters
1Integrative Research Laboratories AB, Sweden
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Joakim Tedroff
1Integrative Research Laboratories AB, Sweden
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Peder Svensson
1Integrative Research Laboratories AB, Sweden
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Anne Fagerberg
1Integrative Research Laboratories AB, Sweden
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Malin Edling
1Integrative Research Laboratories AB, Sweden
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Boel Svanberg
1Integrative Research Laboratories AB, Sweden
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Elisabeth Ljung
1Integrative Research Laboratories AB, Sweden
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Jenny Gunnergren
1Integrative Research Laboratories AB, Sweden
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Samantha L McLean
3School of Pharmacy and Medical Sciences, University of Bradford, United Kingdom
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Ben Grayson
4Division of Pharmacy and Optometry, School of Health Sciences, Univ. of Manchester, United Kingdom
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Nagi F Idris
4Division of Pharmacy and Optometry, School of Health Sciences, Univ. of Manchester, United Kingdom
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Joanna C Neill
4Division of Pharmacy and Optometry, School of Health Sciences, Univ. of Manchester, United Kingdom
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Clas Sonesson
1Integrative Research Laboratories AB, Sweden
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Abstract

Here we describe for the first time the distinctive pharmacological profile for IRL752, a new phenyl-pyrrolidine derivative with regio-selective CNS transmission-enhancing properties. IRL752 (3.7-150 μmol/kg, s.c.) was characterised through extensive in vivo studies, using behavioural, tissue neurochemical and gene expression, as well as microdialysis methods. Behaviourally, the compound normalised tetrabenazine-induced hypoactivity, while unable to stimulate basal locomotion in normal animals or to either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across NA- and DA-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related IEGs (immediate early genes) however increased by 1.5- to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600-750% above baseline, while striatal DA remained unaltered and NA rose to ~250%; cortical and hippocampal dialysate ACh increased to ~250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also pro-cognitive 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‑HT7 receptor and α2(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 where these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson's Disease.

  • acetylcholine
  • alpha-adrenergic receptors
  • behavioral pharmacology
  • brain/CNS
  • cognition
  • Dopamine
  • microdialysis
  • noradrenaline
  • Parkinson's Disease
  • serotonin receptors
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
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Journal of Pharmacology and Experimental Therapeutics: 381 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 2
1 May 2022
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OtherDrug Discovery and Translational Medicine

IRL752 - a cortical-preferring cognition-promoting agent

Stephan Hjorth, Susanna Waters, Nicholas Waters, Joakim Tedroff, Peder Svensson, Anne Fagerberg, Malin Edling, Boel Svanberg, Elisabeth Ljung, Jenny Gunnergren, Samantha L McLean, Ben Grayson, Nagi F Idris, Joanna C Neill and Clas Sonesson
Journal of Pharmacology and Experimental Therapeutics June 30, 2020, JPET-AR-2020-000037; DOI: https://doi.org/10.1124/jpet.120.000037

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OtherDrug Discovery and Translational Medicine

IRL752 - a cortical-preferring cognition-promoting agent

Stephan Hjorth, Susanna Waters, Nicholas Waters, Joakim Tedroff, Peder Svensson, Anne Fagerberg, Malin Edling, Boel Svanberg, Elisabeth Ljung, Jenny Gunnergren, Samantha L McLean, Ben Grayson, Nagi F Idris, Joanna C Neill and Clas Sonesson
Journal of Pharmacology and Experimental Therapeutics June 30, 2020, JPET-AR-2020-000037; DOI: https://doi.org/10.1124/jpet.120.000037
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