Abstract
Transient receptor potential melastatin 8 (TRPM8) is a cold sensitive member of transient receptor potential ion channels. It is expressed by a subset of primary sensory neurons of the dorsal root and trigeminal ganglia and plays an important role in temperature sensation. Beyond cold temperature, several cooling agents, like menthol or icilin, also activate the channel. Here we report a chemically new class of agonists on the basis of macrocyclic lactone ring. In patch clamp and calcium imaging we found that the investigated compounds can activate the human recombinant TRPM8 overexpressed in HEK293T cells which activity was blocked by the TRPM8 antagonist N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride (AMTB). Some of the tested compounds were even more effective than the prototypic TRPM8 agonist menthol. Investigating various analogs, we identified a key motif of the compounds crucial in TRPM8 activation. Moreover, testing various mutants, we also identified amino acid residues forming the binding sites for these novel agonists on TRPM8. Investigating the native TRPM8 expressed by mouse sensory neurons we concluded that the most effective model compound is not only more potent but even more selective than menthol. Our results identified excellent chemical tools to study TRPM8 related functions and also highlight their potential pharmacological use.
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