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Pharmacological characterization of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro-1H-inden-2-yl]-2-propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator

Ward, Simon, Beswick, Paul, Calcinaghi, Novella, Dawson, Lee A, Gartlon, Jane, Graziani, Francesca, Jones, Declan N C, Lacroix, Laurent, Selina Mok, M H, Oliosi, Beatrice, Pardoe, Joanne, Starr, Kathryn, Woolley, Marie L and Harries, Mark H 2017. Pharmacological characterization of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro-1H-inden-2-yl]-2-propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator. British Journal of Pharmacology 174 (5) , pp. 370-385. 10.1111/bph.13696

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Abstract

BACKGROUND AND PURPOSE AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application. EXPERIMENTAL APPROACH [N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro 1H–inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent. KEY RESULTS We demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native heterooligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor-mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay-induced deficit in novel object recognition in rats after both acute and sub-chronic dosing. Subchronic dosing reduced the minimum effective dose from 0.3 to 0.03mg·kg�1. UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine-impaired rats and water maze learning and retentionin aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock thresholdtest at doses below 10 mg·kg�1. CONCLUSION AND IMPLICATIONS We conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Nature Publishing Group
ISSN: 0007-1188
Date of First Compliant Deposit: 8 October 2018
Date of Acceptance: 11 December 2016
Last Modified: 10 Oct 2018 02:05
URI: http://orca-mwe.cf.ac.uk/id/eprint/109251

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