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

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) was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drug-like agents to 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: activity, efficacy, pharmacokinetics and mechanism of action of the molecule. Toxicological and safety studies in animals and humans demonstrated tolerability of the molecule. Key Results VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of multiple sclerosis. This occurred with over a thousand-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that were easily achievable and safe in humans. Interestingly, VSN16R did not bind to known CB1/CB2/GPPR55 cannabinoid-related receptors in receptor-based assays, but was found to act on a vascular cannabinoid target. This was identified to be the major neuronal form of the big conductance, calcium-activated potassium (BKCa) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization to limit excessive neural-excitability and control spasticity. Conclusions and Implications This study identifies a novel role of BKCa channels, a novel mechanism to control spasticity and identifies a new, safe and selective type of ligand to control neural hyper-excitability in spasticity and a number of other neurological conditions.