Allosteric Targeting of Cannabinoid CB1 Receptor to Develop Non-Addictive Small Molecule Analgesics

美国继续面临前所未有的阿片类药物公共卫生危机，导致了巨大的发病率和死亡率，并给社会带来了巨大的成本，而正在进行的COVID- 19大流行进一步加剧了这一危机。持续严重依赖阿片类药物治疗慢性疼痛是造成这一重大问题的主要原因。在这里，我们建议使用一种针对大麻素CB1受体的变构位点的新策略来开发缺乏与阿片类药物相关的有害副作用的非成瘾性镇痛药。虽然CB1受体被正位激动剂激活，如德尔塔-9-四氢大麻酚（THC），在广泛的疼痛模型中产生有效的抗痛觉作用，但这些药物也会引起不必要的大麻模拟副作用以及滥用和依赖。相比之下，CB1受体阳性变构调节剂（pam）为治疗疼痛提供了治疗收益的希望，同时大大降低了大麻模拟、滥用和依赖效应的风险。早期代CB1 PAMs在临床前病理疼痛模型中显示出良好的抗痛觉作用，而不会引起中枢神经系统不良反应，也不会导致重复给药后的耐受或依赖；然而，这些配体的结构为药物的发现和开发带来了隐患。因此，我们的实验室已经生产了一类新型的CB1 pam，其中先导化合物诱导了强大的CB1变构激活，并提供了一种新的支架来增加药理学设计的灵活性，以提供增强的药物性和抗伤害性功效，而不会产生类似大麻的副作用和滥用/依赖性。UG3阶段包含三个具体目标。Aim 1的研究优化了新型CB1 PAMs，验证了靶标结合，并进行了药代动力学和代谢稳定性研究。在目标2中，我们将评估CB1 PAMs在疼痛与大麻模拟副作用、滥用倾向和依赖倾向的小鼠模型中的作用。在第三阶段（UG3期）。目的3将研究miRNA作为变构活化CB1受体的潜在生物标志物。最后，UH3阶段的目标4将进行药物开发的ind研究。该项目的目标是在临床前研究中推进选定的CB1 PAM作为非成瘾性非阿片类镇痛药治疗慢性疼痛，并支持未来的IND临床研究。

the U.S. continues to face an unprecedented opioid public health crisis that has resulted in tremendous morbidity and mortality, as well as a significant cost to society, which has been further exacerbated by the on-going COVID- 19 pandemic. Continual, heavy reliance on opioids to treat chronic pain has been a major contributor to this major problem. Here, we propose to develop non-addictive analgesics that lack the deleterious side effects associated with opioids using a new strategy that targets allosteric sites of the cannabinoid CB1 receptor. While CB1 receptor activation by orthosteric agonists, such as delta-9-tetrahydrocannabinol (THC), produces potent antinociceptive effects in a wide range of pain models, these drugs also elicit unwanted cannabimimetic side effects as well as abuse and dependence liability. In contrast, CB1 receptor positive allosteric modulators (PAMs) offer promise of therapeutic gain to treat pain with substantially diminished risk of cannabimimetic, abuse, and dependence effects. Early generation CB1 PAMs showed promising antinociceptive effects in preclinical models of pathological pain without inducing CNS adverse effects or resulting in tolerance or dependence following repeated administration; however, the structures of these ligands presented pitfalls for drug discovery and development. Thus, our laboratories have produced a novel class of CB1 PAMs in which the lead compound induces robust CB1 allosteric activation and provides a novel scaffold to increase pharmacological design flexibility to provide enhanced druggability and antinociceptive efficacy without cannabimimetic side effects and abuse/dependence liability. The UG3 phase contains three specific aims. Studies in Aim 1 optimize novel CB1 PAMs, verify target engagement, and conduct pharmacokinetic and metabolic stability studies. In Aim 2, we will evaluate CB1 PAMs in mouse models of pain versus cannabimimetic side effects, abuse liability, and dependence liability. In Aim 3 (UG3 phase). Aim 3 will investigate miRNA as potential biomarkers for allosterically activated CB1 receptors. Finally, aim 4 in the UH3 phase will pursue IND-enabling studies towards drug development. The goal of this project is to advance a selected CB1 PAM in preclinical studies as a non-addictive, non-opioid analgesic to treat chronic pain and support future IND clinical investigation.