Biasing Mu Opioid Receptor Signaling in vivo

摘要 处方类阿片类麻醉药，如吗啡、羟考酮和芬太尼，产生止痛和副作用。 通过激活Mu阿片受体(MOR)，一种G蛋白偶联受体(GPCR)而发挥作用。我们的长- 长期的目标是了解MOR信号如何产生不同的生物效应，并最终 影响将利用“好的”受体信号(缓解疼痛)的治疗方法的发展 并避免导致不必要的阿片类药物副作用的“坏”受体信号，如呼吸抑制和 宽容。越来越明显的是，不同的药物结构可以引起不同的受体。 信号在单个受体上级联，可能是通过改变与细胞内联系的亲和力 有约束力的伙伴。在过去的十年里，我们已经开发出一系列的激动剂，它们的作用方式是 驱动G蛋白信号传导至MOR下游，并在受体和受体之间产生少量相互作用 抑制蛋白2，一种支架蛋白。此外，我们已经确定其中几种激动剂会产生 不会引起呼吸抑制的抗伤害作用。一种化合物SR-17108已被证明是 在神经病理性疼痛模型中，它的效果比羟考酮或吗啡更好。 在小鼠模型中，SR-17018的慢性治疗不会导致耐受性。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 受体上的不同部位，因此是非竞争性或变构激动剂。在这项提案中，我们 想要确定是这种非竞争性特性，还是其他药理特性 化合物具有赋予良好生理特性的物质。此外，我们正在寻求确定 这些化合物的结合部位。因为这些化合物与受体上的不同部位结合 传统的阿片类药物，我们将询问变构化合物如何与吗啡、芬太尼和 纳洛酮同时给药时。

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.