Novel Probes of the Kappa Opioid Receptor: Chemistry, Pharmacology, and Biology

描述（由申请人提供）：我们建议开发新的kappa阿片受体（KOR）调节剂，用于治疗成瘾和情绪障碍的早期发展。Dynorphins是应激肽，作用于KOR。因此，为了抑制dynorphin介导的作用，需要寻找KOR的负调节因子。有大量证据表明，KOR通过β抑制蛋白2介导某些副作用（镇静和烦躁不安），并通过G蛋白介导其镇痛和止痒作用。因此，我们建议开发能够拮抗βarrestin2相互作用受体的化合物。具体来说，我们的目标是：1。竞争性拮抗剂能有效抑制β捕集蛋白2的募集；2. 在阻断dynorphin刺激的βarrestin2募集同时保留G蛋白信号的完全激动作用方面具有潜在竞争的部分激动剂；3. 负变构调节剂会降低KOR对肌啡肽的反应性。在本提案中，我们介绍了我们在引入第一个小分子G蛋白偏向性KOR激动剂方面取得的广泛进展的最新进展。我们还提供了大量的初步数据，支持开发上述拮抗剂、偏倚部分激动剂和负变构调节剂的成功活动。特别是，负变构调制器将

DESCRIPTION (provided by applicant): We propose to develop new kappa opioid receptor (KOR) modulators for early stage development towards treating addictive and mood disorders. Dynorphins are stress peptides and act at the KOR. Therefore, to suppress dynorphin-mediated effects, negative regulators of KOR are sought. There is considerable evidence that KOR signals through βarrestin2 to mediate certain side effects (sedation and dysphoria) and through G proteins to mediate its analgesic and antipruritic effects. Therefore, we propose to develop compounds that antagonize the βarrestin2-interacting receptor. Specifically we aim to deliver: 1. Competitive antagonists that are potent and efficacious in suppressing βarrestin2 recruitment; 2. Partial agonists that are potently competitive at blocking dynorphin-stimulated βarrestin2 recruitment while preserving full agonism in G protein signaling; 3. Negative allosteric modulators that will decrease KOR responsiveness to dynorphins. In this proposal, we present an update on the extensive progress we have made in introducing the first small molecule, G protein biased KOR agonists to the field. We also provide substantial preliminary data supporting a successful campaign to develop the aforementioned antagonists, biased partial agonists and negative allosteric modulators. In particular, the negative allosteric modulators will be "first in class" for this receptor. This proposal seeks 5 years of support to provide the initia preclinical characterizations and chemical optimizations of these compounds into drug candidates. In line with this goal, we will fully characterize the pharmacological properties of th compounds across functionally diverse cell-based assays with of a goal of identifying compounds capable of fine-tuning KOR responsiveness. Cell-based responses will be validated in mouse models assessing locomotor responses, antinociceptive activity and suppressing pruritis (itch response) to determine that compound maintains the pharmacological profiles in vivo. Drug metabolism and pharmacokinetics of the compounds will be performed to provide information for continued medicinal chemistry optimization rounds and to advance compounds to clinical development. Our enthusiastic team consists of established medicinal and synthetic chemists; an opioid neuropharmacologist (with both molecular and behavioral pharmacology expertise); and an expert in pharmacokinetics and drug metabolism. The development of pharmacological tools across diverse pharmacophores and correlating their properties with in vivo response profiles will provide guiding evidence of the optimal chemical and pharmacological properties required to produce the desired physiological responses.