Pain Research, Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
J Pharmacol Exp Ther. 2011 Mar;336(3):743-50. doi: 10.1124/jpet.110.175570. Epub 2010 Nov 22.
Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal pain models; however, some compounds induce hyperthermia in animals and humans. We discovered the novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in our laboratory. AS1928370 bound to the resiniferatoxin-binding site on TRPV1 and inhibited capsaicin-mediated inward currents with an IC₅₀ value of 32.5 nM. Although AS1928370 inhibited the capsaicin-induced Ca²(+) flux in human and rat TRPV1-expressing cells, the inhibitory effect on proton-induced Ca²(+) flux was extremely small. In addition, AS1928370 showed no inhibitory effects on transient receptor potential vanilloid 4, transient receptor potential ankyrin 1, and transient receptor potential melastatin 8 in concentrations up to 10 μM. AS1928370 improved capsaicin-induced secondary hyperalgesia and mechanical allodynia in an L5/L6 spinal nerve ligation model in rats with respective ED₅₀ values of 0.17 and 0.26 mg/kg p.o. Furthermore, AS1928370 alleviated inflammatory pain in a complete Freund's adjuvant model at 10 mg/kg p.o. AS1928370 had no effect on rectal body temperature up to 10 mg/kg p.o., although a significant hypothermic effect was noted at 30 mg/kg p.o. In addition, AS1928370 showed no significant effect on motor coordination. These results suggest that blockage of the TRPV1 receptor without affecting the proton-mediated TRPV1 activation is a promising approach to treating neuropathic pain because of the potential wide safety margin against hyperthermic effects. As such, compounds such as ASP1928370 may have potential as new analgesic agents for treating neuropathic pain.
瞬时受体电位香草酸 1 型（TRPV1）可被多种刺激激活，如内源性配体和低 pH 值，并被认为在疼痛传递中起作用。已经报道 TRPV1 拮抗剂在几种动物疼痛模型中有效；然而，一些化合物会在动物和人类中引起发热。我们在实验室中发现了新型 TRPV1 拮抗剂（R）-N-（1-甲基-2-氧代-1,2,3,4-四氢-7-喹啉基）-2-[[2-甲基吡咯烷-1-基]甲基]联苯-4-甲酰胺（AS1928370）。AS1928370 与 TRPV1 的树脂毒素结合位点结合，并以 32.5 nM 的 IC₅₀ 值抑制辣椒素介导的内向电流。尽管 AS1928370 抑制了人源和大鼠 TRPV1 表达细胞中辣椒素诱导的 Ca²（+）流，但对质子诱导的 Ca²（+）流的抑制作用极小。此外，AS1928370 在高达 10 μM 的浓度下对瞬时受体电位香草酸 4、瞬时受体电位锚蛋白 1 和瞬时受体电位 melastatin 8 没有抑制作用。AS1928370 以 0.17 和 0.26 mg/kg p.o. 的各自 ED₅₀ 值改善了 L5/L6 脊神经结扎大鼠模型中辣椒素诱导的继发性痛觉过敏和机械性痛觉过敏。此外，AS1928370 以 10 mg/kg p.o. 的剂量减轻完全弗氏佐剂模型中的炎症性疼痛。AS1928370 对直肠体温的影响最高可达 10 mg/kg p.o.，但在 30 mg/kg p.o. 时则明显出现降温作用。此外，AS1928370 对运动协调没有明显影响。这些结果表明，阻断 TRPV1 受体而不影响质子介导的 TRPV1 激活是治疗神经病理性疼痛的一种很有前途的方法，因为其对发热作用具有潜在的宽安全范围。因此，像 AS1928370 这样的化合物可能有潜力成为治疗神经病理性疼痛的新型镇痛剂。
