Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Neuropharmacology. 2017 Nov;126:97-107. doi: 10.1016/j.neuropharm.2017.08.032. Epub 2017 Aug 30.
Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE-, PGF-, and AMPA-induced allodynia, while both pregabalin and duloxetine alleviated only PGE-induced allodynia in mice. Similarly, AS2717638 significantly ameliorated static mechanical allodynia and thermal hyperalgesia in rat models of chronic constriction injury (CCI)-induced neuropathic pain. AS2717638 also showed analgesic effects in a rat model of inflammatory pain. These findings suggest that LPA5 antagonists elicit broad analgesic effects against both neuropathic and inflammatory pain. Accordingly, pharmacological LPA5 antagonists are attractive development candidates for potential novel pain therapies.
溶血磷脂酸（LPA）是一种生物活性脂质，通过至少六个 G 蛋白偶联受体（LPA1-6）发挥作用，具有各种生理功能。我们研究了（1）LPA5 是否参与脊髓中的疼痛信号传递；（2）新型 LPA5 拮抗剂对鞘内前列腺素（PG）和（S）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）诱导的痛觉过敏以及啮齿动物的神经性和炎性疼痛的药理学作用。鞘内注射选择性 LPA5 激动剂 geranylgeranyl diphosphate 和非选择性激动剂 LPA 可诱导野生型小鼠出现痛觉过敏，但 LPA5 敲除小鼠则无此现象。这些新结果表明，LPA5 对脊髓中的疼痛信号传递很重要。AS2717638（6,7-二甲氧基-2-（5-甲基-1,2-苯并恶唑-3-基）-4-（哌啶-1-基羰基）异喹啉-1（2H）-酮）与 LPA5 的 LPA 结合位点结合，并选择性抑制人 LPA5-但不 LPA1、2 或 3 表达细胞中的 LPA 诱导的环腺苷酸积累。此外，AS2717638 可抑制鞘内 LPA5 激动剂诱导的小鼠痛觉过敏。AS2717638 还显著改善 PGE、PGF 和 AMPA 诱导的痛觉过敏，而普瑞巴林和度洛西汀仅可缓解 PGE 诱导的痛觉过敏。同样，AS2717638 显著改善慢性缩窄性损伤（CCI）诱导的神经性疼痛大鼠模型中的静态机械性痛觉过敏和热痛觉过敏。AS2717638 在炎性疼痛的大鼠模型中也显示出镇痛作用。这些发现表明，LPA5 拮抗剂可针对神经性和炎性疼痛产生广泛的镇痛作用。因此，药理学 LPA5 拮抗剂是开发新型潜在疼痛疗法的有吸引力的候选药物。
