Development of LPA5 Antagonists as Analgesics

神经性疼痛是一种令人虚弱和复杂的医疗状况，在美国和 全球范围内。阿片类药物是临床上最常用的止痛药；然而，他们的物理 依赖和滥用责任构成了严重的公共卫生挑战，并给 社会。显然，迫切需要更安全的非阿片类止痛药。溶血磷脂酸受体5(LPA5， 以前称为孤儿受体GPR92)在与疼痛处理相关的组织中高度表达，如 脊髓和背根神经节(DRG)。LPA5受体的激活或上调在 对神经损伤和多发性硬化症引起的神经病理性疼痛的反应。LPA5的遗传性KO或阻断 拮抗剂AS2717638对神经性冷痛或机械性痛觉过敏有明显的镇痛作用 损伤以及佐剂诱导的炎症性疼痛，而LPA5 KO小鼠的正常痛感没有改变。 这些结果有力地支持了LPA5作为新的止痛靶点和LPA5拮抗剂作为新的镇痛剂。 现有证据表明，LPA5的止痛作用是通过背根节和脊髓背角来实现的，尽管 LPA5在神经病理性疼痛的这两个区域的表达和功能尚未被研究。此外, AS2717638作为迄今为止唯一一种被检测为痛觉调制的LPA5拮抗剂，在体内表现为中度 在神经病理性和炎症性疼痛模型中，32 mg/kg的大剂量未能完全逆转 疼痛过敏，强调了优化这一有希望的导联和/或鉴定LPA5的必要性 基于新型支架的拮抗剂。为此，我们计划研究基因的表达和功能 LPA5在脊髓和背根节的表达，以进一步验证LPA5在神经病理性疼痛中的作用 AIM 1中的药理工具，并通过文库筛选和虚拟筛选鉴定新的LPA5拮抗剂 在目标2中，我们的目标是确定至少两个系列的LPA5拮抗剂，以便在Fugure U19中进行进一步的优化 相位。

Neuropathic pain is a debilitating and complex medical condition and afflicts millions of people in the US and globally. Opioids are the most clinically used analgesics for pain management; however, their physical dependence and abuse liability pose serious public health challenges and mounting economic burdens to the society. There is clearly an urgent need for safer non-opioid analgesics. Lysophosphatidic acid receptor 5 (LPA5, previously known as orphan receptor GPR92) is highly expressed in tissues related to pain processing such as spinal cord and dorsal root ganglion (DRG). Activation or upregulation of the LPA5 receptor is observed in response to nerve injury- and multiple sclerosis-induced neuropathic pains. Genetic KO or blockade of LPA5 by antagonist AS2717638 displayed significant analgesia against cold or mechanical allodynia induced by nerve injury as well as adjuvant induced inflammatory pain, while normal pain sensation in LPA5 KO mice is not altered. These results strongly supporting LPA5 as a novel analgesic target and LPA5 antagonists as novel analgesics. Existing evidence suggests medication of LPA5 analgesic effects via DRG and spinal cord dorsal horn, although the LPA5 expression and function in these two regions in neuropathic pain have not been examined. In addition, AS2717638, as the only LPA5 antagonist examined for pain modulation thus far, showed moderate in vivo potency in both neuropathic and inflammatory pain models, where a high dose of 32 mg/kg failed to fully reverse pain hypersensitivity, highlighting the need for optimization of this promising lead and/or identification of LPA5 antagonists based on novel scaffolds. Towards this end, we plan to examine the expression and function of LPA5 in spinal cord and DRG to further validate the role of LPA5 in neuropathic pain using genetic and pharmacological tools in Aim 1 and identify novel LPA5 antagnist hits via library screening and virtual screening in Aim 2. Our goal is to identify at least two series of LPA5 antagonists for further optimization in the fugure U19 phase.