Chronic pain—including migraines, diabetic neuropathy, sciatica, and chemotherapy-induced neuralgia—has long affected hundreds of millions of patients worldwide. Existing analgesics, such as aspirin, ibuprofen, pregabalin, acetaminophen, and opioids, offer limited efficacy against chronic pain and are oftenaccompanied by side effects such as gastrointestinal damage, hepatotoxicity, nephrotoxicity, sedation, drowsiness, and addiction risks. Consequently, the development of safe and efficient novel non-opioid analgesics has become an urgent clinical need.

Recently, a collaborative team from the School of Basic Medical Sciences, the Second Affiliated Hospital, and the School of Life Sciences of Nanchang University, together with Shenzhen Jingdan Biomedical Technology Company, Gannan Medical University, and Zhujiang Hospital of Southern Medical University, published a research paper online in Neuron titled: "Cryo-EM Structure enabling virtual screening for the discovery of highly potent TRPM3 antagonists with analgesic efficacy."The research team first resolved the high-resolution cryo-electron microscopy (cryo-EM) structure of human TRPM3. They identified a small-molecule binding pocket within its voltage-sensor-like domain (VSLD). By combining large-scale virtual screening with structural optimization, the team developed TRPM3 antagonists with inhibitory activity reaching the picomolar level.This molecule demonstrated significant dose-dependent analgesic effects in various neuropathic pain and migraine animal models,without affecting motor function, demonstrating good efficacy and safety.

TRPM3 belongs to the Transient Receptor Potential (TRP) ion channel family, primarily expressed in sensory neurons, involved in the perception of noxious heat stimuli, and plays a key role in neuropathic and inflammatory pain.Inhibiting TRPM3 produces significant analgesic effects.

At the same time, this channel is downstream of the opioid signaling pathway, and its antagonists do not cause hyperthermia.This makes it an ideal target for non-opioid pain analgesics. However, a long-standing lack of high-resolution structural information has severely hindered the drug development process.

Using cryo-electron microscopy (cryo-EM), the research team resolved the TRPM3 structure and identified a narrow small-molecule binding pocket within its voltage-sensor-like domain (VSLD).Based on this structural information, the researchers screened and optimized from a vast library of compounds to obtain ultra-high-potency antagonists. This molecule has high selectivity for TRPM3, with no significant effects on other TRP channels, and exhibits favorable pharmacokinetic properties.

In various animal models of chronic pain, the compound demonstrated exceptional therapeutic results compared to current "gold standard" treatments.In multiple chronic pain animal models, the compound demonstrated remarkable therapeuticefficacy;In neuropathic pain models, its analgesic effect was superior to that of pregabalin; In diabetic neuropathy models, it acted rapidly and with sustained effects; In nitroglycerin-induced acute migraine models, its efficacy was comparable to that of the CGRP antagonist rimegepant; And in inflammatory pain models, it outperformed ibuprofen. Safety assessments further showed that the molecule does not affect motor coordination or spontaneous activity, and has no significant inhibition of the hERG channel, suggesting a low risk of cardiovascular toxicity.

This study establishes an integrated "Structure Resolution — Virtual Screening — Functional Validation" pipeline. This not only provides a vital strategy for developing highly selective non-opioid analgesics but also serves as a valuable paradigm for the development of drugs targeting other complex ion channels.

Dr. YangTingting, Dr. CheTong, Dr. GuoHongmin, and Dr. Cheng Xinyu of Nanchang University, and Wang Mingyang (Master) of Zhujiang Hospital of Southern Medical University, are the co-first authors of the paper.Professor ZhangJin, Professor DuanJingjing, and Professor Li Guilin of Nanchang University; Professor Li Jian of Gannan Medical University; and Professor Li Fengxian of Zhujiang Hospital of Southern Medical University are the corresponding authors.

Paper link:

https://linkinghub.elsevier.com/retrieve/pii/S0896627325010025