Discovery and pharmacological characterization of novel positive allosteric modulators acting on skeletal muscle-type nicotinic acetylcholine receptors

Skeletal muscle-type nicotinic acetylcholine receptors (m-nAChRs) are ligand-gated ion channels that open after activation by ACh and whose signals cause muscle contraction. Defects in neurotransmission are reported in disorders such as myasthenia gravis (MG) and congenital myasthenia syndromes (CMS). Although treatments for these disorders exist, therapies which significantly increase muscle strength have yet to be reported. Positive allosteric modulators (PAMs), which promote ACh signaling through AChRs, are expected to be promising therapeutic agents. In this study, we identified an m-nAChR PAM called AS3513678 by high-throughput screening using human myotube cells and modified it to obtain novel compounds (AS3566987 and AS3580239) that showed even stronger PAM activity. AS3580239 caused a leftward shift in the ACh concentration-response curve and was 14.0-fold potent at 10 μM compared with vehicle. Next, we examined the effect of AS3580239 on electrically-induced isometric contraction of the extensor digitorum longus (EDL) muscle in wild-type (WT) and MG model rats. AS3580239 enhanced EDL muscle contraction in both WT and MG model rats at 30 μM. These data suggest that AS3580239 improved neurotransmission and enhanced muscle strength. Thus, m-nAChR PAMs may be a useful treatment for neuromuscular diseases. •There are currently no satisfactory drugs for neuromuscular diseases.•We found new positive allosteric modulators which act on skeletal muscle-type nAChRs.•The compounds induce a leftward shift in the ACh concentration in human myotube cells.•The compounds enhance contraction of muscles in a rat model of myasthenia gravis.•The positive allosteric modulator may be a promising drug for neurological disorders.