Post-stroke muscle spasticity affects 37% of stroke survivors and disables self-supporting life management. There is a high unmet medical need for an efficient antispastic drug because current muscle relaxants are often of limited efficacy and cause severe neurological and cardiovascular side effects due to targeting the central or peripheral nervous system. We developed a new-generation anti-spastic oral drug, MPH-220, which efficiently relaxes spastic skeletal muscles and lacks cardiovascular and neurological adverse effects because it selectively targets skeletal myosin, the contractile protein of muscles. MPH-220 is an efficient skeletal muscle specific actomyosin relaxant demonstrated on human muscle samples. Orally administered MPH-220 reduces muscle force of living rats without cardiovascular side effects. Brain-damage induced spastic animals showed drastic improvement in gait disorders upon oral MPH-220 treatment resulting in significantly straightened body posture, reduced number of spontaneous falling and cramping, and more ordered limb positions. Due to selective accumulation of MPH-220 in skeletal muscle tissues, antispastic effect was maintained for more than 10 hours. Due to its mechanism of action MPH-220 does not cause complete loss of muscle tone even at high doses. Furthermore, MPH-220 has excellent ADMET properties for oral administration: it is highly absorptive, non-mutagenic and has no effects on hERG channels, kinases, nuclear hormone receptors and GPCRs. Considering these results, MPH-220 is a promising anti-spastic oral drug candidate, which provides potential nervous system-independent therapies for spasticity and muscle stiffness without cardiovascular and neuronal side effects. Phase I clinical trials are scheduled for the beginning of 2021. Funded by the Hungarian National Research, Development and Innovation Office (NVKP 16-1-2016-0051 and PIACI-KFI-2019-00488).
Basic Aspects of the Pharmacodynamics of Tolperisone, A Widely Applicable Centrally Acting Muscle Relaxant
