García-Martinez Carolina, Humet Marc, Planells-Cases Rosa, Gomis Ana, Caprini Marco, Viana Felix, De La Pena Elvira, Sanchez-Baeza Francisco, Carbonell Teresa, De Felipe Carmen, Pérez-Paya Enrique, Belmonte Carlos, Messeguer Angel, Ferrer-Montiel Antonio
Centro de Biología Molecular y Celular, Universidad Miguel Hernández, Alicante, Spain.
Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2374-9. doi: 10.1073/pnas.022285899.
Vanilloid receptor subunit 1 (VR1) appears to play a critical role in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues. Thus, VR1 antagonists are useful compounds to unravel the contribution of this receptor to pain perception, as well as to induce analgesia. We have used a combinatorial approach to identify new, nonpeptidic channel blockers of VR1. Screening of a library of trimers of N-alkylglycines resulted in the identification of two molecules referred to as DD161515 [N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] and DD191515 [[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide] that selectively block VR1 channel activity with micromolar efficacy, rivaling that characteristic of vanilloid-related inhibitors. These compounds appear to be noncompetitive VR1 antagonists that recognize a receptor site distinct from that of capsaicin. Intraperitoneal administration of both trialkylglycines into mice significantly attenuated thermal nociception as measured in the hot plate test. It is noteworthy that these compounds eliminated pain and neurogenic inflammation evoked by intradermal injection of capsaicin into the animal hindpaw, as well as the thermal hyperalgesia induced by tissue irritation with nitrogen mustard. In contrast, responses to mechanical stimuli were not modified by either compound. Modulation of sensory nerve fibers excitability appears to underlie the peptoid analgesic activity. Collectively, these results indicate that blockade of VR1 activity attenuates chemical and thermal nociception and hyperalgesia, supporting the tenet that this ionotropic receptor contributes to chemical and thermal sensitivity and pain perception in vivo. These trialkylglycine-based, noncompetitive VR1 antagonists may likely be developed into analgesics to treat inflammatory pain.
香草酸受体亚基1（VR1）似乎在外周组织中感觉神经末梢传导有害化学和热刺激方面发挥着关键作用。因此，VR1拮抗剂是用于阐明该受体对痛觉的作用以及诱导镇痛的有用化合物。我们采用了一种组合方法来鉴定新的非肽类VR1通道阻滞剂。对N-烷基甘氨酸三聚体文库进行筛选，结果鉴定出两种分子，分别称为DD161515 [N-[2-(2-(N-甲基吡咯烷基)乙基]甘氨酰]-[N-[2,4-二氯苯乙基]甘氨酰]-N-(2,4-二氯苯乙基)甘氨酰胺]和DD191515 [[N-[3-(N,N-二乙氨基)丙基]甘氨酰]-[N-[2,4-二氯苯乙基]甘氨酰]-N-(2,4-二氯苯乙基)甘氨酰胺]，它们以微摩尔效力选择性地阻断VR1通道活性，与香草酸相关抑制剂的特性相当。这些化合物似乎是非竞争性VR1拮抗剂，识别与辣椒素不同的受体位点。将这两种三烷基甘氨酸腹腔注射到小鼠体内，在热板试验中显著减轻了热痛觉。值得注意的是，这些化合物消除了皮内注射辣椒素到动物后爪所诱发的疼痛和神经源性炎症，以及氮芥刺激组织所诱导的热痛觉过敏。相比之下，两种化合物对机械刺激的反应均未产生改变。感觉神经纤维兴奋性的调节似乎是类肽镇痛活性的基础。总体而言，这些结果表明，阻断VR1活性可减轻化学性和热性痛觉及痛觉过敏，支持了这种离子型受体在体内对化学和热敏感性及痛觉起作用的观点。这些基于三烷基甘氨酸的非竞争性VR1拮抗剂可能会被开发成治疗炎性疼痛的镇痛药。
