Biasing Mu Opioid Receptor Signaling in vivo

体内 Mu 阿片受体信号传导偏向

• 批准号: 10682557
• 负责人: Laura M. Bohn
• 金额: $ 45.67万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682557
• 关键词: Absence of pain sensation; Acute; Adverse effects; Adverse event; Affinity; Agonist; Analgesics; Behavior; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Cells; Cellular Membrane; Chemicals; Chronic; Detection; Development; Dose; Fentanyl; Funding; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Hyperactivity; Laboratories; Libraries; Ligands; Measurement; Measures; Molecular; Morphine; Motor Activity; Mus; Naloxone; Narcotics; Opioid; Opioid Analgesics; Opioid agonist; Oxycodone; Paclitaxel; Pain; Pharmaceutical Preparations; Pharmacology; Physiological; Pre-Clinical Model; Primates; Property; Receptor Signaling; Reporting; Resistance; Rodent; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Signaling Protein; Site; Site-Directed Mutagenesis; System; Testing; Therapeutic; allodynia; antinociception; drug action; drug structure; in vivo; mouse model; mu opioid receptors; novel strategies; novel therapeutics; opioid overdose; pain model; pain relief; painful neuropathy; pharmacologic; preference; prescription opioid; preservation; radioligand; receptor; recruit; respiratory; response; scaffold; side effect; therapeutic development; treatment response

Summary Prescription opioid narcotics, such as morphine, oxycodone, and fentanyl, produce analgesia and side effects through activation of the mu opioid receptor (MOR), a G protein coupled receptor (GPCR). Our long- standing goal is to understand how MOR signals to produce distinct biological effects and to ultimately influence the development of therapeutics that will take advantage of “good” receptor signaling (pain relief) and avoid “bad” receptor signaling that leads to unwanted opioid side effects like respiratory suppression and tolerance. It has become increasingly evident that different drug structures can elicit different receptor signaling cascades at a single receptor, likely by changing the affinities for association with intracellular binding partners. Over the past decade, we have developed a series of agonists that act in a manner that drives G protein signaling downstream of MOR and induce little interactions between the receptor and arrestin2, a scaffolding protein. Moreover, we have determined that several of these agonists produce antinociception without inducing respiratory suppression. One compound, SR-17108 has been shown to be potent and efficacious in a neuropathic pain model where it performed better than oxycodone or morphine. Chronic treatment with SR-17018 did not lead to tolerance in the mouse models. Extensive biochemical studies have recently revealed that at least 4 agonists from this class, including SR-17018, are binding to different sites on the receptor and are therefore noncompetitive or allosteric agonists. In this proposal, we want to determine if it is this noncompetitive property, or other pharmacological properties that the compounds possess that confer the favorable physiological profiles. Further, we are seeking to determine the binding site of these compounds. Since the compounds bind to different sites on the receptor than conventional opioid drugs, we will ask how the allosteric compounds interact with morphine, fentanyl and naloxone when administered together.

总结 处方阿片类麻醉剂，如吗啡，羟考酮和芬太尼，产生镇痛和副作用， 通过激活μ阿片受体（莫尔）（一种G蛋白偶联受体（GPCR））发挥作用。我们长久以来- 长期目标是了解莫尔信号如何产生不同的生物学效应，并最终 影响将利用“良好”受体信号传导（缓解疼痛）的治疗方法的发展 并避免“坏”受体信号，导致不必要的阿片类药物副作用，如呼吸抑制， 宽容越来越明显的是，不同的药物结构可以诱导不同的受体， 信号级联在一个单一的受体，可能是通过改变亲和力的协会与细胞内 有约束力的伙伴在过去的十年里，我们已经开发了一系列激动剂，其作用方式是 驱动莫尔下游的G蛋白信号传导，并诱导受体和 抑制蛋白2，一种支架蛋白。此外，我们已经确定这些激动剂中的几种产生 不引起呼吸抑制的抗伤害感受。一种化合物SR-17108已被证明是 在神经病理性疼痛模型中，它比羟考酮或吗啡表现得更好。 SR-17018长期给药未导致小鼠模型耐受。广泛的生物化学 最近的研究表明，至少有4种这类激动剂，包括SR-17018，与 受体上的不同位点，因此是非竞争性或变构激动剂。在本提案中，我们 我想确定是否是这种非竞争性的性质，或其他药理学性质， 这些化合物具有赋予有利的生理特征。此外，我们正在努力确定 这些化合物的结合位点。由于化合物与受体上的不同位点结合， 常规阿片类药物，我们将询问变构化合物如何与吗啡，芬太尼和 纳洛酮一起给药。

项目成果

Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists.

• DOI: 10.1021/acs.biochem.1c00466
• 发表时间: 2022-09-20
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Stahl EL;Bohn LM
• 通讯作者: Bohn LM