Chemoreactome analysis of tolperisone, tizanidine, and baclofen molecules: anticholinergic, antispasmodic, and analgesic mechanisms of action

Muscle relaxants are used in the treatment of musculoskeletal pain. The exact molecular mechanisms of action of muscle relaxants are not always clear. Some muscle relaxants show mainly an anticholinergic effect, others have GABAergic one; they differ in accumulation in muscles, central nervous system, and other tissues. Objective: to carry out a comparative chemoreactome analysis of tolperisone with tizanidine and baclofen, allowing the pharmacological action of each of the molecules to be specified. Material and methods . The investigators applied a chemoinformational approach, i.e. compared the chemical structure of the studied molecules with the structures of millions of other molecules, for which the molecular and pharmacological properties are known. The analysis is based on the latest machine learning technologies developed within the framework of the theory of combinatorial solvability analysis, the theory of topological and metric approaches to analyzing the features of the so-called big data. Results and discussion . Tolperisone was most likely to accumulate in the skeletal muscles, adrenal cortex, and hypothalamus. The drug caused a muscle relaxant effect through cholinergic action, practically without affecting adrenergic, dopaminergic, GABAergic neurotransmission. Each of the studied molecules was established to exert dose-dependent antispasmodic and analgesic effects. Tolperisone was shown to have antithrombotic and antiinflammatory effects due to inhibition of the activity of tumor necrosis factor-a and to modulation of the metabolism ofprostaglandins and leukotrienes. Conclusion. Significant differences were found in the mechanisms of molecular action of tolperisone, tizanidine, and baclofen, which was responsible for differences in the time of onset and duration of action of a muscle relaxant, in the action on CNS or peripheral nervous system neurons, as well as in additionalpleiotropic effects and adverse reactions.