Development of MRGPRX1 positive allosteric modulators as non-addictive therapies for neuropathic pain

项目摘要 神经性疼痛仍然是一种具有挑战性的疾病，因为目前所有可用的药物都无法达到治疗目的。 相当一部分患者的疼痛得到了充分的缓解。尽管阿片类止痛药已经被 事实证明，对于许多神经性疼痛情况，它们在减轻疼痛强度方面是有效的，其临床实用价值是 由于这类治疗所涉及的重大风险，包括恶心、便秘、身体 依赖性、耐受性和呼吸抑制。显然，有一种严重的未得到满足的医疗需求 改善疗效和副作用的神经病理性疼痛治疗。累积的证据表明 人类Mas相关G蛋白偶联受体X1(MRGPRX1)是有希望的有限疼痛的靶点 由于其在周围神经系统的伤害性感受器中的表达受到限制而产生的副作用。BAM8-22，a 推测为内源性MRGPRX1激动剂，已在以下各种疼痛模型中显示出镇痛效果 鞘内注射。虽然这些发现开启了中枢神经系统穿透小分子的有趣可能性 MRGPRX1激动剂用于治疗疼痛，在外周终端直接激活MRGPRX1是 预计会引起瘙痒副作用，限制了正位MRGPRX1激动剂的治疗作用。 有趣的是，作为内源性MRGPRX1正构体的BAM22衍生多肽的次最大水平 在持续疼痛期间，在脊髓背角检测到激动剂，但在 皮肤。这一发现导致了对MRGPRX1的正变构调节剂(PAM)的探索 增强感觉神经元中枢终末内源性激动剂的作用 激活外设MRGPRX1。事实上，鞘内注射原型MRGPRX1 PAM，ML382， 有效缓解诱发性、持续性和自发性疼痛，且不会引起瘙痒副作用。因此， 这项建议的中心目标是开发一种CNS穿透性小分子MRGPRX1 PAM，可以给出 口服治疗神经病理性疼痛的情况。为了实现组装IND应用程序的最终目标， 一支具有互补专业知识的独立调查团队已经组建了多年的 在药物化学、ADME、神经科学、临床前疼痛模型和 临床疼痛管理。根据这项里程碑式的阶段性合作协议，该团队将努力 与NIH项目工作人员密切合作，加快MRGPRX1的优化和开发 PAM是一种非成瘾性治疗剂，用于治疗神经病理性疼痛状况。

Project Summary Neuropathic pain remains a challenging condition to treat, as all currently available drugs fail to achieve adequate pain relief in a significant proportion of patients. Although opioid-based analgesics have been proven effective in reducing the intensity of pain for many neuropathic pain conditions, their clinical utility is grossly limited due to the substantial risks involved in such therapy, including nausea, constipation, physical dependence, tolerance, and respiratory depression. Clearly, there is a critical unmet medical need for new neuropathic pain therapies with improved efficacy and side effect profiles. Cumulative evidence suggests that human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain with limited side effects due to its restricted expression in nociceptors within the peripheral nervous system. BAM8-22, a putative endogenous MRGPRX1 agonist, has shown analgesic efficacy in a variety of pain models following intrathecal injection. While these findings open up the intriguing possibility for CNS-penetrant small molecule MRGPRX1 agonists for the treatment of pain, direct activation of MRGPRX1 at peripheral terminals is expected to induce itch side effects, limiting the therapeutic utility of orthosteric MRGPRX1 agonists. Interestingly, submaximal levels of BAM22-derived peptides acting as endogenous MRGPRX1 orthosteric agonists were detected at the spinal cord dorsal horn during persistent pain but remained undetectable in the skin. This finding led to the exploration of positive allosteric modulators (PAMs) of MRGPRX1 to potentiate the effects of the endogenous agonists at the central terminals of sensory neurons without activating peripheral MRGPRX1. Indeed, intrathecal injection of a prototype MRGPRX1 PAM, ML382, effectively attenuated evoked, persistent, and spontaneous pain without causing itch side effects. Thus, the central goal of this proposal is to develop a CNS-penetrant small molecule MRGPRX1 PAM that can be given orally to treat neuropathic pain conditions. To accomplish the ultimate goal of assembling an IND application, a team of independent investigators with complementary expertise has been assembled with many years of research experience in the areas of medicinal chemistry, ADME, neuroscience, preclinical pain models, and clinical pain management. Under this milestone-driven phased cooperative agreement, the team will work closely with NIH program staff to accelerate the optimization and development of a promising MRGPRX1 PAM lead into a non-addictive therapeutic agent for the treatment of neuropathic pain conditions.