Development of LPA5 Antagonists as Analgesics

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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.