Big conductance calcium-activated potassium channel openers control spasticity without sedation.
Big conductance calcium-activated potassium channel openers control spasticity without sedation.
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DOI：
10.1111/bph.13889
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发表时间：
2017-08
影响因子：
7.3
通讯作者：
Selwood DL
中科院分区：
文献类型：
--
作者：
Baker D;Pryce G;Visintin C;Sisay S;Bondarenko AI;Vanessa Ho WS;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
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. 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. 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. 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.
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DOI：
10.1124/jpet.108.144717
发表时间：
2009-01
影响因子：
3.5
作者：
Godlewski, Grzegorz;Offertaler, Laszlo;Osei-Hyiaman, Douglas;Mo, Fong Ming;Harvey-White, Judith;Liu, Jie;Davis, Margaret I.;Zhang, Li;Razdan, Raj K.;Milman, Garry;Pacher, Pal;Mukhopadhyay, Partha;Lovinger, David M.;Kunos, George
通讯作者：
Kunos, George
影响因子：
7.3
作者：
Bondarenko, Alexander I.;Drachuk, Konstantin;Graier, Wolfgang F.
通讯作者：
Graier, Wolfgang F.
影响因子：
4.7
作者：
Chen SR;Cai YQ;Pan HL
通讯作者：
Pan HL
影响因子：
13.8
作者：
Baker, D;Pryce, G;Hiley, CR
通讯作者：
Hiley, CR
影响因子：
4
作者：
Al-Izki, Sarah;Pryce, Gareth;Baker, David
通讯作者：
Baker, David