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

摘要: Background & Purpose The initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis, whilst avoiding the sedative, side-effect-potential associated with cannabis. (R,Z)-3-(6-(dimethylamino)-6-oxohex-1-enyl)-N-(1-hydroxypropan-2-yl)benzamide (VSN16R) synthesized an anandamide (endocannabinoid) analogue in anti-metabolite approach identify drug-like target spasticity. Experimental Approach Following chemistry, variety biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays vivo animal models, were used demonstrate: activity, efficacy, pharmacokinetics mechanism action molecule. Toxicological safety studies animals humans demonstrated tolerability molecule. Key Results VSN16R had nanomolar activity tissue-based, functional dose-dependently inhibited spasticity mouse experimental encephalomyelitis model sclerosis. This occurred over thousand-fold therapeutic window, without affecting normal muscle tone. Efficacy achieved at plasma levels easily achievable safe humans. Interestingly, VSN16R did not bind known CB1/CB2/GPPR55 cannabinoid-related receptors receptor-based assays, but found act on vascular target. identified be major neuronal form big conductance, calcium-activated potassium (BKCa) channel. Drug-induced opening BKCa channels induced membrane hyperpolarization limit excessive neural-excitability spasticity. Conclusions Implications This study identifies novel role channels, new, selective type ligand neural hyper-excitability number other neurological conditions.