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

TY - JOUR

T1 - Pharmacological characterisation of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro-1H-inden-2-yl]-2-propanesulfonamide

T2 - a novel, clinical AMPA receptor positive allosteric modulator

AU - Ward, Simon E

AU - Beswick, Paul

AU - Calcinaghi, Novella

AU - Dawson, Lee A

AU - Gartlon, Jane

AU - Graziani, Francesca

AU - Jones, Declan N C

AU - Lacroix, Laurent

AU - Mok, M H Selina

AU - Oliosi, Beatrice

AU - Pardoe, Joanne

AU - Starr, Kathryn

AU - Woolley, Marie L

AU - Harries, Mark H

N1 - © 2016 The British Pharmacological Society. The attached document (embargoed until 31/01/2018) is an author produced version of a paper published in the British Journal of Pharmacology and uploaded in accordance with the publisher’s self- archiving policy. The final published version (version of record) is available online at http://dx.doi.org/10.1111/bph.13696. Some minor differences between this version and the final published version may remain. We suggest you refer to the final published version should you wish to cite from it.

PY - 2017/2/10

Y1 - 2017/2/10

N2 - 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.

AB - 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.

U2 - 10.1111/bph.13696

DO - 10.1111/bph.13696

M3 - Article

C2 - 28009436

SN - 1476-5381

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

ER -