{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T04:58:27Z","timestamp":1781499507068,"version":"3.54.1"},"reference-count":68,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2017,7,7]],"date-time":"2017-07-07T00:00:00Z","timestamp":1499385600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["FWF; P 27238"],"award-info":[{"award-number":["FWF; P 27238"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000396","name":"Technology Strategy Board","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000396","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310030_152578"],"award-info":[{"award-number":["310030_152578"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000381","name":"Multiple Sclerosis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000381","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000368","name":"Brain Research Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000368","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>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\u2010metabolite approach to identify drugs that target spasticity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue\u2010based assays and <jats:italic>in vivo<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>VSN16R had nanomolar activity in tissue\u2010based, functional assays and dose\u2010dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000\u2010fold 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 CB<jats:sub>1<\/jats:sub>\/CB<jats:sub>2<\/jats:sub>\/GPPR55 cannabinoid\u2010related receptors in receptor\u2010based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium\u2010activated potassium (BK<jats:sub>Ca<\/jats:sub>) channel. Drug\u2010induced opening of neuronal BK<jats:sub>Ca<\/jats:sub> channels induced membrane hyperpolarization, limiting excessive neural\u2010excitability and controlling spasticity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>We identified the neuronal form of the BK<jats:sub>Ca<\/jats:sub> 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\u2010excitability in spasticity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13889","type":"journal-article","created":{"date-parts":[[2017,7,5]],"date-time":"2017-07-05T10:13:43Z","timestamp":1499249623000},"page":"2662-2681","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Big conductance calcium\u2010activated potassium channel openers control spasticity without sedation"],"prefix":"10.1111","volume":"174","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8872-8711","authenticated-orcid":false,"given":"David","family":"Baker","sequence":"first","affiliation":[{"name":"Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"},{"name":"Department of Neuroinflammation, UCL Institute of Neurology University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth","family":"Pryce","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"},{"name":"Department of Neuroinflammation, UCL Institute of Neurology University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Visintin","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, UCL Institute of Neurology University College London  London UK"},{"name":"Department of Medicinal Chemistry, UCL Wolfson Institute for Biomedical Research University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Sisay","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander I","family":"Bondarenko","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Biochemistry Medical University of Graz  Graz Austria"},{"name":"A.A. Bogomoletz Institute of Physiology  Kiev Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W S","family":"Vanessa Ho","sequence":"additional","affiliation":[{"name":"Vascular Biology Research Centre. St. George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J","family":"Jackson","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E","family":"Williams","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Al\u2010Izki","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Sevastou","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, UCL Wolfson Institute for Biomedical Research University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Okuyama","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, UCL Wolfson Institute for Biomedical Research University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang F","family":"Graier","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Biochemistry Medical University of Graz  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley A","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Vascular Biology Research Centre. St. George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Tanner","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Institute of Medical Sciences University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Institute of Medical Sciences University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger G","family":"Pertwee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Institute of Medical Sciences University of Aberdeen  Aberdeen UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M","family":"Henstridge","sequence":"additional","affiliation":[{"name":"Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J","family":"Irving","sequence":"additional","affiliation":[{"name":"Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School University of Dundee  Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Schulman","sequence":"additional","affiliation":[{"name":"Canbex Therapeutics Ltd London BioScience Innovation Centre  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Powell","sequence":"additional","affiliation":[{"name":"Canbex Therapeutics Ltd London BioScience Innovation Centre  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D","family":"Baker","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Giovannoni","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London  London UK"},{"name":"Department of Neuroinflammation, UCL Institute of Neurology University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L","family":"Selwood","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, UCL Wolfson Institute for Biomedical Research University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,7,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13347"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13348"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13350"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13349"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2011.09.001"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt324"},{"key":"e_1_2_10_8_1","unstructured":"Allen mouse spinal cord atlas. (2008). Available at:http:\/\/www.brain\u2010map.org\/ (accessed 21\/6\/2017)"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/35003583"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2005.11.003"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2011.11.001"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/0888439002250449"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00976.2012"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307258200"},{"key":"e_1_2_10_15_1","first-page":"281","article-title":"Development of a novel class of monocyclic and bicyclic alkyl amides that exhibit CB1 and CB2 cannabinoid receptor affinity and receptor activation","volume":"16","author":"Berglund BA","year":"2000","journal-title":"Drug Des Discov"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12866"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-010-0898-x"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12180"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/35038011"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1573"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2009.12.002"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06138.x"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)08220-X"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12856"},{"key":"e_1_2_10_25_1","unstructured":"FreemanTC DixonAK CampbellEA TaitTM RichardsonPJ RiceKMet al. (1998).Expression mapping of mouse genes. MGI Direct Data Submission J:46439."},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1114321109"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.144717"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/86546"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.5402\/2012\/802649"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707141"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707470"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.54.2.161"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.143933"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.2170\/jjphysiol.47.11"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205795200"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2010.11.024"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-015-7878-1"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00788.2003"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1177\/0333102414534083"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201411253"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.29.3.201"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12955"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-11-44"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00007"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00373"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2010.03328.x"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.14.7.885"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00622.x"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.003004"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awg224"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-239442"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703850"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471141755.ph1010s27"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2014.02.016"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401702101"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0157754"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD001332"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076907"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1037"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0114328"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/354906"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.080739"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-10-03563.2000"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0702127"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756285615601390"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5362.443"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00401"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00006.2012"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbph.13889","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.13889","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T16:40:21Z","timestamp":1696264821000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.13889"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,7]]},"references-count":68,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2017,8]]}},"alternative-id":["10.1111\/bph.13889"],"URL":"https:\/\/doi.org\/10.1111\/bph.13889","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,7]]},"assertion":[{"value":"2017-01-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-05-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-07-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}