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

David Baker; Gareth Pryce; Cristina Visintin; Sofia Sisay; Alexander I. Bondarenko; W. S. Vanessa  Ho; Samuel J. Jackson; Thomas E. Williams; Sarah Al-Izki; Ioanna Sevastou; Masahiro Okuyama; Wolfgang F. Graier; Lesley A. Stevenson; Carolyn Tanner; Ruth Ross; Roger G. Pertwee; Christopher M. Henstridge; Andrew J. Irving; Jesse Schulman; Keith Powell; Mark D. Baker; Gavin Giovannoni; David L. Selwood

doi:10.1111/bph.13889

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

David Baker (Lead / Corresponding author), Gareth Pryce, Cristina Visintin, Sofia Sisay, Alexander I. Bondarenko, W. S. Vanessa Ho, Samuel J. Jackson, Thomas E. Williams, Sarah Al-Izki, Ioanna Sevastou, Masahiro Okuyama, Wolfgang F. Graier, Lesley A. Stevenson, Carolyn Tanner, Ruth Ross, Roger G. Pertwee, Christopher M. Henstridge, Andrew J. Irving, Jesse Schulman, Keith PowellMark D. Baker, Gavin Giovannoni, David L. Selwood

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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.

Original language	English
Pages (from-to)	2662-2681
Number of pages	20
Journal	British Journal of Pharmacology
Volume	174
Issue number	16
Early online date	5 Jul 2017
DOIs	https://doi.org/10.1111/bph.13889
Publication status	Published - Aug 2017

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© 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 medium, provided the original work is properly cited.
Final published version, 1.62 MBLicence: CC BY

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Baker, D., Pryce, G., Visintin, C., Sisay, S., Bondarenko, A. I., Ho, W. S. V., Jackson, S. J., Williams, T. E., Al-Izki, S., Sevastou, I., Okuyama, M., Graier, W. F., Stevenson, L. A., Tanner, C., Ross, R., Pertwee, R. G., Henstridge, C. M., Irving, A. J., Schulman, J., ... Selwood, D. L. (2017). Big conductance calcium-activated potassium channel openers control spasticity without sedation. British Journal of Pharmacology, 174(16), 2662-2681. https://doi.org/10.1111/bph.13889

@article{2b6399fdf9a341ff8efb0586dd61b7c2,

title = "Big conductance calcium-activated potassium channel openers control spasticity without sedation",

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.",

author = "David Baker and Gareth Pryce and Cristina Visintin and Sofia Sisay and Bondarenko, {Alexander I.} and Ho, {W. S. Vanessa} and Jackson, {Samuel J.} and Williams, {Thomas E.} and Sarah Al-Izki and Ioanna Sevastou and Masahiro Okuyama and Graier, {Wolfgang F.} and Stevenson, {Lesley A.} and Carolyn Tanner and Ruth Ross and Pertwee, {Roger G.} and Henstridge, {Christopher M.} and Irving, {Andrew J.} and Jesse Schulman and Keith Powell and Baker, {Mark D.} and Gavin Giovannoni and Selwood, {David L.}",

note = "The authors are grateful for the support of the Austrian Science Funds (FWF; P 27238), BioTechMed, Brain Research Trust, the Multiple Sclerosis Society, the Blo omsbury Bioseed Fund, Esparant eVentures, the Wellcome Trust, University College London Business, Fastforward USA, MS Ventures, Swiss National Science Foundation grant (#310030_152578) and the Technology Strategy Board UK/Innovate UK.",

year = "2017",

month = aug,

doi = "10.1111/bph.13889",

language = "English",

volume = "174",

pages = "2662--2681",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "Wiley",

number = "16",

}

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', British Journal of Pharmacology, vol. 174, no. 16, pp. 2662-2681. https://doi.org/10.1111/bph.13889

TY - JOUR

T1 - Big conductance calcium-activated potassium channel openers control spasticity without sedation

AU - Baker, David

AU - Pryce, Gareth

AU - Visintin, Cristina

AU - Sisay, Sofia

AU - Bondarenko, Alexander I.

AU - Ho, W. S. Vanessa

AU - Jackson, Samuel J.

AU - Williams, Thomas E.

AU - Al-Izki, Sarah

AU - Sevastou, Ioanna

AU - Okuyama, Masahiro

AU - Graier, Wolfgang F.

AU - Stevenson, Lesley A.

AU - Tanner, Carolyn

AU - Ross, Ruth

AU - Pertwee, Roger G.

AU - Henstridge, Christopher M.

AU - Irving, Andrew J.

AU - Schulman, Jesse

AU - Powell, Keith

AU - Baker, Mark D.

AU - Giovannoni, Gavin

AU - Selwood, David L.

N1 - The authors are grateful for the support of the Austrian Science Funds (FWF; P 27238), BioTechMed, Brain Research Trust, the Multiple Sclerosis Society, the Blo omsbury Bioseed Fund, Esparant eVentures, the Wellcome Trust, University College London Business, Fastforward USA, MS Ventures, Swiss National Science Foundation grant (#310030_152578) and the Technology Strategy Board UK/Innovate UK.

PY - 2017/8

Y1 - 2017/8

N2 - 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.

AB - 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.

U2 - 10.1111/bph.13889

DO - 10.1111/bph.13889

M3 - Article

C2 - 28677901

SN - 0007-1188

VL - 174

SP - 2662

EP - 2681

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 16

ER -

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

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