Pharmacological characterisation 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

Simon E Ward, Paul Beswick, Novella Calcinaghi, Lee A Dawson, Jane Gartlon, Francesca Graziani, Declan N C Jones, Laurent Lacroix, M H Selina Mok, Beatrice Oliosi, Joanne Pardoe, Kathryn Starr, Marie L Woolley, Mark H Harries

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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 pre-clinical 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 hetero-oligomeric AMPARs UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPAR-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 (NOR) in rats after both acute and sub-chronic dosing. Sub-chronic dosing reduced the minimum effective dose from 0.3 mg/kg to 0.03 mg/kg. UoS12258 was also effective at improving performance in two other cognition models i.e. passive avoidance in scopolamine-impaired rats and water maze learning and retention in aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold (MEST) test at doses below 10 mg/kg.

CONCLUSION AND IMPLICATIONS: We conclude that UoS12258 is a potent and selective AMPAR modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules which have previously entered clinical evaluation. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalBritish Journal of Pharmacology
Early online date31 Jan 2017
DOIs
Publication statusPublished - 10 Feb 2017

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