Pharmacological Activity of Motugivatrep, a Novel Antagonist of Transient Receptor Potential Cation Channel Subfamily V Member 1

Abstract

Transient receptor potential (TRP) cation channel subfamily V member 1 (TRPV1) is predominantly expressed in sensory neurons and activated by nociceptive stimuli, including capsaicin, heat, and acidic conditions. Recent research has highlighted the role of TRPV1 in the pathophysiology of dry eye disease (DED). This study evaluated the antagonistic activity and TRP channel selectivity of motugivatrep, a novel TRPV1 antagonist. The inhibitory effects of motugivatrep were assessed in cells expressing various TRP channels as well as in rat dorsal root ganglion (DRG) cells, with agonist-induced intracellular Ca²⁺ influx used as an indicator. Off-target effects were evaluated using comprehensive Cerep pharmacology profiling, which included radiolabeled ligand-binding assays for major ion channels, receptors, and enzyme assays. Motugivatrep exhibited pronounced inhibition of capsaicin-stimulated TRPV1 across multiple species, with IC₅₀ values ranging from 0.46 to 2.1 nM. Furthermore, although motugivatrep exhibited weak inhibition of human TRPV4, it had no significant effects on TRPV3, TRPA1, or TRPM8. Additionally, motugivatrep suppressed capsaicin-induced intracellular Ca²⁺ influx in DRG cells (IC₅₀ = 2.8 nM). Off-target profiling revealed minimal binding to 5-HT_2A and 5-HT_2B receptors. Overall, these findings indicate that motugivatrep is a potent and highly selective TRPV1 antagonist, supporting its potential as a therapeutic candidate for disorders associated with TRPV1 activation, such as DED.