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个具有挑战性的条件，以治疗，因为所有目前可用的药物未能实现 大部分患者的疼痛得到充分缓解。虽然阿片类镇痛药已经被 已证明其在降低许多神经性疼痛病症的疼痛强度方面是有效的， 由于这种治疗涉及的实质性风险，包括恶心、便秘、身体不适、 依赖、耐受和呼吸抑制。显然，新的医疗需求严重未得到满足， 具有改善的功效和副作用特征的神经性疼痛疗法。累积的证据表明 人Mass相关G蛋白偶联受体X1（MRGPRX 1）是一个有前途的疼痛靶点， 由于其在外周神经系统内的伤害感受器中的受限表达而引起的副作用。BAM 8 -22，a 一种假定的内源性MRGPRX 1激动剂，已在多种疼痛模型中显示出镇痛功效， 鞘内注射虽然这些发现为CNS渗透小分子开辟了有趣的可能性， 用于治疗疼痛的MRGPRX 1激动剂，在外周末端直接激活MRGPRX 1， 预期会诱导瘙痒副作用，限制了正构MRGPRX 1激动剂的治疗效用。 有趣的是，作为内源性MRGPRX 1正构蛋白的次最大水平的BAM 22衍生肽， 在持续性疼痛期间，在脊髓背角检测到激动剂，但在 皮肤这一发现导致了对MRGPRX 1的正变构调节剂（PAM）的探索， 增强内源性激动剂在感觉神经元中枢末梢的作用， 激活外周MRGPRX 1。实际上，鞘内注射原型MRGPRX 1 PAM，ML 382， 有效地减弱诱发的、持续的和自发的疼痛，而不引起瘙痒副作用。因此 该建议的中心目标是开发一种CNS渗透剂小分子MRGPRX 1 PAM， 口服以治疗神经性疼痛病症。为了实现组装IND应用程序的最终目标， 一个由独立调查人员组成的小组，具有互补的专业知识， 在药物化学，ADME，神经科学，临床前疼痛模型等领域的研究经验， 临床疼痛管理根据这一里程碑式的分阶段合作协议， 与NIH项目人员密切合作，加速有前途的MRGPRX 1的优化和开发 PAM导致成为用于治疗神经性疼痛病症的非成瘾性治疗剂。

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.