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

大麻素 CB1 受体变构靶向开发非成瘾性小分子镇痛药

• 批准号: 10512672
• 负责人: Dai Lu
• 金额: $ 290.31万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512672
• 关键词: Adverse effects; Adverse event; Agonist; Allosteric Site; Analgesics; Animals; Binding; Biological Markers; CNR1 gene; COVID-19 pandemic; Cannabinoids; Cannabis; Centers for Disease Control and Prevention (U.S.); Clinical; Contractor; Dependence; Desire for food; Development; Drug Kinetics; Drug Targeting; Economic Burden; Epidemic; Face; Formulation; Future; Generations; Goals; In Vitro; Investigation; Investigational Drugs; Laboratories; Lead; Ligands; Memory; Memory impairment; Metabolic; MicroRNAs; Moods; Morbidity - disease rate; Nervous system structure; Opioid; Outcome; Oxycodone; Pain; Pathologic; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Pre-Clinical Model; Process; Property; Public Health; Rattus; Receptor Activation; Reporting; Research; Rewards; Risk; Societies; Structure; Testing; Tetrahydrocannabinol; Therapeutic; Time; Toxicology; Translating; United States National Institutes of Health; Work; abuse liability; addiction; base; biomarker validation; cannabimimetics; chronic pain management; clinical application; clinical investigation; cost; design; drug candidate; drug development; drug discovery; efficacy study; flexibility; in vivo; lead candidate; lead optimization; microRNA biomarkers; mortality; mouse model; non-opioid analgesic; novel; novel strategies; opioid epidemic; opioid use; opioid use disorder; pain model; pain sensation; positive allosteric modulator; potential biomarker; pre-clinical; preclinical evaluation; preclinical study; prescription opioid; presynaptic neurons; receptor; response; scaffold; side effect; small molecule; social; success; targeted biomarker

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.

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，以及社会的重大成本，而持续的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一直是这一重大问题的主要原因。在这里，我们建议开发非成瘾性镇痛药，缺乏与阿片类药物相关的有害副作用，使用一种新的策略，靶向大麻素CB 1受体的变构位点。虽然通过正构激动剂（如δ-9-四氢大麻酚（THC））的CB 1受体活化在广泛的疼痛模型中产生有效的抗伤害感受作用，但这些药物也引起不想要的拟大麻副作用以及滥用和依赖倾向。相比之下，CB 1受体阳性变构调节剂（PAM）提供了治疗疼痛的治疗收益的承诺，大大降低了大麻类药物，滥用和依赖性效应的风险。早期的CB 1 PAM在病理性疼痛的临床前模型中显示出有希望的抗伤害感受作用，而不会诱导CNS不良反应或导致重复给药后的耐受性或依赖性;然而，这些配体的结构为药物发现和开发提供了陷阱。因此，我们的实验室已经产生了一类新型的CB 1 PAM，其中先导化合物诱导稳健的CB 1变构激活，并提供了一种新的支架，以增加药理学设计的灵活性，从而提供增强的可药用性和抗伤害性功效，而没有大麻模拟副作用和滥用/依赖倾向。UG 3阶段包含三个具体目标。目标1中的研究优化了新型CB 1 PAM，验证了靶标接合，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CB 1 PAM在小鼠模型中的疼痛与拟大麻副作用，滥用倾向和依赖倾向。目标3（UG 3阶段）。目的3研究miRNA作为变构激活的CB 1受体的潜在生物标志物。最后，UH 3阶段的目标4将继续进行IND使能研究，以进行药物开发。该项目的目标是在临床前研究中推进选定的CB 1 PAM作为一种非成瘾性、非阿片类镇痛药，用于治疗慢性疼痛，并支持未来的IND临床研究。