β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14894 - 14894

Published: Oct. 4, 2023

The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca2+)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel featuring C-terminal amides diversely substituted N'-terminal monobenzyl groups an attempt to increase total polar surface area (TPSA) this family compounds. primary goal was assess influence these substituents on inhibition menthol-induced cellular Ca2+ entry, thereby establishing critical structure-activity relationships. While substitution tert-butyl ester by isobutyl amide moieties improved activity, none N'-monobencyl derivatives, regardless substituent phenyl ring, achieved activity model dibenzyl compound. potency most effective compounds subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, evaluated selectivity one against other members (TRP) some receptors connected peripheral pathways. compound demonstrated specificity for channels. To better comprehend mode interaction, conducted docking experiments uncover plausible binding sites functionally active tetrameric protein. four main populated poses are located pore zone, similar location described N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) cannot be discarded. Finally, vivo experiments, involving couple selected compounds, revealed significant antinociceptive within mice cold allodynia induced oxaliplatin (OXA).

Language: Английский

TRPM8 channels, cold and headache: data of experimental and clinical studies

Успехи физиологических наук, Journal Year: 2024, Volume and Issue: 55(3), P. 112 - 122

Published: Nov. 5, 2024

Abstract – Different types of headaches, including migraine, may have a causal relationship with cold exposure, and this can be either positive or negative, i.e. both provoke alleviate cephalalgia. Various representatives the transient receptor potential ion channel superfamily, in particular TRPM8, act as molecular thermoreceptors that provide signal transduction response to low temperatures. These channels, which are known mediate normal sensation play role cold-induced pain cryoanalgesia, often considered promising target for development principally new anti-migraine drugs. This review summarizes recently obtained data on TRPM8 structure function, their pathogenesis well discusses intriguingly inconsistent results studying agonists antagonists experimental headache models clinical trials. Analyzing from various studies allows conclude activation pro- antinociceptive; correlates reported dual effect exposure induction resolution leaving open question vector pharmacological modulation required produce anticephalgic effect.

Language: Английский

The neurotrophin artemin and its receptor GFRα3 mediate migraine-like pain via the ion channel TRPM8

Published: Sept. 13, 2024

Migraine has a strong genetic foundation, including both monogenic and polygenic types. The former are rare, with most migraine considered polygenic, supported by genome-wide association studies (GWAS) identifying numerous variants associated risk. Surprisingly, some of the common mutations TRPM8, non-selective cation channel that is primary sensor cold temperatures in afferent neurons somatosensory system. However, it unlikely temperature sensitivity TRPM8 underlies its role pathogenesis. To define basis channel's involvement, we reasoned cellular processes increase skin, such as neurotrophin artemin, via receptor GFRα3, also mediate TRPM8-associated migraine-like pain meninges.

Language: Английский