通过快速电流脱敏,发现具有抗nociceptive作用的非电友TRPA1通道激动剂
Nan Yang1, Zhen Qiao2, Qiqi Zhou3
1Departments of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, Qingdao University Medical College, Qingdao, 266073, China.
European journal of medicinal chemistry
|April 10, 2025
概括
为短暂受体潜在氨酸1 (TRPA1) 通道开发非电友性激素加速了脱敏,为减少刺激的新型止痛药提供了一种战略. 复合体21显示出作为主要候选人的承诺.
科学领域:
- 药理学 药理学是指药理学的学科.
- 神经科学是一个神经科学.
- 分子生物学分子生物学
背景情况:
- 通过激动剂激活短暂受体潜能安基林1 (TRPA1) 通道是止痛药开发的关键策略.
- 电友性TRPA1激动剂,如BITC和乙胺,与氨酸残留物结合,引起刺激.
- 电友激动剂的刺激性质是开发有效止痛药的重要限制.
研究的目的:
- 设计和合成新的非电友TRPA1激动剂,以减轻刺激.
- 调查非电友性激动剂是否可以加速TRPA1脱敏,从而增强镇痛效果.
- 在体内评估新型TRPA1激动剂的止痛和刺激性质.
主要方法:
- 通过修改电友性JT010结构来设计和合成新型TRPA1激动剂.
- 全细胞补丁电生理学评估TRPA1激动剂活性,选择性和脱敏动力学.
- 在小鼠体内进行疼痛和刺激试验,以评估化合物的有效性和安全性.
主要成果:
- 化合物21被确定为具有强烈活性的选择性TRPA1激动剂 (hTRPA1的EC50 = 25.47 ± 1.56μM).
- 化合物21与电友性激动剂JT010和BITC相比,显示出TRPA1脱敏率明显更快 (τ = 20.02 ± 1.66秒).
- 化合物21在小鼠中表现出有效的止痛特性,而不会引起刺激.
结论:
- 非电友性TRPA1激动剂可以加速通道脱敏,增强抗nociceptive效果.
- 化合物21代表了一种有前途的化合物,用于开发具有更好的安全概况的TRPA1向止痛药.
- 针对TRPA1脱敏提供了一个可行的治疗策略来治疗疼痛.
更多相关视频
08:35A Simple and Inexpensive Method for Determining Cold Sensitivity and Adaptation in Mice
Published on: March 17, 2015
14.7K
09:39Establishing a Mouse Model of a Pure Small Fiber Neuropathy with the Ultrapotent Agonist of Transient Receptor Potential Vanilloid Type 1
Published on: February 13, 2018
9.5K
相关概念视频
01:44Nociception
27.6K
Nociception—the ability to feel pain—is essential for an organism’s survival and overall well-being. Noxious stimuli such as piercing pain from a sharp object, heat from an open flame, or contact with corrosive chemicals are first detected by sensory receptors, called nociceptors, located on nerve endings. Nociceptors express ion channels that convert noxious stimuli into electrical signals. When these signals reach the brain via sensory neurons, they are perceived as pain.
27.6K
01:25Analgesia and Pain Management
403
Pain is critical to various clinical pathologies, provoking an urgent need for effective management. Pain, whether acute or chronic, is a complex neurochemical process. Its alleviation depends on the type, with nonopioid analgesics effective for mild to moderate pain, such as musculoskeletal or inflammatory pain, while neuropathic pain responds best to anticonvulsants, tricyclic antidepressants, or serotonin/norepinephrine reuptake inhibitors. For severe acute or chronic pain, opioids may be...
403
01:15Opioid Analgesics: Synthetic and Semisynthetic Opioids
183
Synthetic and semisynthetic opioids are pivotal in pain management and tackling opioid addiction. Semisynthetic opioids, including morphinans (morphine derivatives), oxycodone, oxymorphone, hydrocodone, and hydromorphone, have improved pharmacokinetic profiles compared to morphine. Additionally, heroin and 6-MAM (6-Monoacetylmorphine) show better CNS penetration than morphine due to heightened lipid solubility. Hydromorphone, a potent opioid, undergoes hepatic metabolism to form the active...
183
01:12Mechanically-gated Ion Channels
6.1K
Mechanically-gated ion channels are proteins found in eukaryotic and prokaryotic cell membranes that open in response to mechanical stress. Tension, compression, swelling, and shear stress can alter the conformation of the protein, opening a transmembrane channel that allows the passage of ions for signal transmission. In eukaryotes, mechanically-gated channels are distributed in several regions like the neurons, lungs, skin, bladder, and heart, where they play critical roles in numerous...
6.1K
01:20Pain
412
Pain serves as a critical warning signal that alerts the body to potential or actual harm. When mechanical pressure on the skin is intense, such as from a sharp pinch, the sensation transitions from touch to pain. Similarly, extreme temperatures, like a hot pot handle, convert the sensation of heat into pain. Pain can also result from overstimulation of other senses, such as blinding light, loud noise, or the intense heat from habañero peppers. This ability to sense pain is essential for...
412
01:28Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists
144
Neurokinin 1 (NK1) receptors are distributed across the GI tract, vagal afferents, and key CNS regions including the central vomiting center and chemoreceptor trigger zone (CTZ) Chemotherapy agents stimulate enterochromaffin cells in the gastrointestinal (GI) tract to release large amounts of substance P (SP). SP is a neuropeptide released by specific sensory nerves in response to many different stressors, including those in the GI mucosa affected by chemotherapy. SP binds and activates...
144