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

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    Publication date
    2020-09
    Author
    Hjorth, S.
    Waters, S.
    Waters, N.
    Tedroff, J.
    Svensson, P.
    Fagerberg, A.
    Edling, M.
    Svanberg, B.
    Ljung, E.
    Gunnergren, J.
    McLean, Samantha L.
    Grayson, B.
    Idris, N.F.
    Neill, J.C.
    Sonesson, C.
    Show allShow less
    Keyword
    Acetylcholine
    Alpha-adrenergic receptors
    Behavioral pharmacology
    Brain/CNS
    Cognition
    Dopamine
    Microdialysis
    Noradrenaline
    Parkinson's Disease
    Serotonin receptors
    Rights
    © 2020 The Author(s). This is an open access article distributed under the CC BY Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
    Peer-Reviewed
    Yes
    
    Metadata
    Show full item record
    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.
    URI
    http://hdl.handle.net/10454/17970
    Version
    Published version
    Citation
    Hjorth S, Waters S, Waters N et al (2020) (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) - a novel cortical-preferring catecholamine transmission- and cognition-promoting agent. Journal of Pharmacology and Experimental Therapeutics. 374(3): 404-419.
    Link to publisher’s version
    https://doi.org/10.1124/jpet.120.000037
    Type
    Article
    Collections
    Life Sciences Publications

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