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Big conductance calcium-activated potassium channel openers control spasticity without sedation.

Baker, D; Pryce, G; Visintin, C; Sisay, S; Bondarenko, AI; Ho, WSV; Jackson, SJ; Williams, TE; Al-Izki, S; Sevastou, I; et al. Baker, D; Pryce, G; Visintin, C; Sisay, S; Bondarenko, AI; Ho, WSV; Jackson, SJ; Williams, TE; Al-Izki, S; Sevastou, I; Okuyama, M; Graier, WF; Stevenson, LA; Tanner, C; Ross, R; Pertwee, RG; Henstridge, CM; Irving, AJ; Schulman, J; Powell, K; Baker, MD; Giovannoni, G; Selwood, DL (2017) Big conductance calcium-activated potassium channel openers control spasticity without sedation. Br J Pharmacol, 174 (16). pp. 2662-2681. ISSN 1476-5381 https://doi.org/10.1111/bph.13889
SGUL Authors: Ho, Wing Sze Vanessa

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Abstract

BACKGROUND AND PURPOSE: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity. EXPERIMENTAL APPROACH: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans. KEY RESULTS: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity. CONCLUSIONS AND IMPLICATIONS: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity.

Item Type: Article
Additional Information: © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any me dium, provided the original work is properly cited.
Keywords: Pharmacology & Pharmacy, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: Br J Pharmacol
ISSN: 1476-5381
Language: eng
Dates:
DateEvent
August 2017Published
5 July 2017Published Online
17 May 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDWellcome Trusthttp://dx.doi.org/10.13039/100004440
P 27238Austrian Science Fundhttp://dx.doi.org/10.13039/501100002428
310030_152578Swiss National Science Foundationhttp://dx.doi.org/10.13039/501100001711
PubMed ID: 28677901
Web of Science ID: WOS:000406141700005
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/109105
Publisher's version: https://doi.org/10.1111/bph.13889

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