Peptidic Ligands for Kappa Opioid Receptors

说明(申请人提供)：虽然吗啡等麻醉性镇痛剂是治疗剧烈疼痛的重要药物，但由于耐受性、呼吸抑制和药物滥用等严重副作用，其使用受到限制。因此，有相当大的兴趣，以确定与降低风险的止痛药临床使用。Kappa阿片受体(KOPr)配体在治疗疼痛方面显示出治疗价值，在治疗情绪障碍和药物滥用方面也具有潜力。因此，探索KOPr活性的结构要求对于开发KOPr配体作为潜在的新药具有重要意义。拟议的研究集中在KOPr的多肽配体上，这些配基的研究还没有像其他阿片受体的多肽那样广泛。我们实验室最近的研究已经成功地发现了一些具有独特药理特征的KOPr多肽配体，它们比目前的KOPr配体具有明显的优势，包括一些在体内具有强大的抗伤害性活性的KOPr配体。因此，在这一竞争性更新应用中拟议的研究的目标是继续我们对KOPr中具有活性的关键多肽配体的结构研究，并扩大这些研究以包括评估多肽在体内的阿片类药物活性。本研究的长期目标是探索具有KOPr活性的多肽配体的结构-活性关系(SAR)，并寻找具有理想药理特性的多肽KOPr配体用于体内。为了实现这些目标，我们将追求三个特定的目标：1)探索新的强啡肽类似物，KOPr的内源性配体；2)探索结构上与强啡肽无关的新的KOPr多肽的SAR；3)利用小鼠的镇痛、抗伤害性耐受、生理反应和位置调节的模型，在体内评价多肽KOPr配体。我们假设，具有混合激动剂/KOPr拮抗剂活性的多肽激动剂将表现出显著的抗伤害作用，易感性降低。这些研究将进一步加深我们对KOPr在各种药理过程中作用的理解，并推动具有治疗应用潜力的KOPr配体的开发。 公共卫生相关性：虽然吗啡等麻醉性镇痛剂已被广泛用于治疗疼痛，但由于其严重的副作用，其使用受到限制。因此，有必要确定具有改善副作用特征的有希望的先导化合物，这些化合物可能导致改善疼痛的治疗。涉及kappa阿片受体的混合活性化合物可能具有镇痛活性且副作用较少，但这些混合活性药物的开发一直受到限制。阻断kappa阿片受体的拮抗剂也可能在治疗情绪障碍和药物滥用方面具有潜力。临床上需要这些药物，如本提案中所述，可用作药理工具和进一步开发的先导化合物。

DESCRIPTION (provided by applicant): While narcotic analgesics such as morphine are important drugs for the treatment of severe pain, their use is limited because of serious side effects such as tolerance, respiratory depression, and the potential for drug abuse. Thus there is considerable interest in identifying analgesics with reduced liabilities for clinical use. Kappa opioid receptor (KOPr) ligands have shown therapeutic value in the treatment of pain, and potential for the treatment of mood disorders and drug abuse as well. Therefore exploring the structural requirements for KOPr activity is important to developing KOPr ligands as potential new medications. The proposed research focuses on peptide ligands for KOPr, which have not been studied as extensively as peptides for other opioid receptors. Recent studies in our laboratories have successfully identified a number of KOPr peptide ligands with unique pharmacological profiles that offer distinct advantages over current KOPr ligands, including some with potent antinociceptive activity in vivo. Therefore the goals of the proposed research in this competitive renewal application are to continue our structural studies of key peptidic ligands with activity at KOPr and to expand these studies to include evaluating peptides for opioid activity in vivo. The long term objectives of this research are to explore the structure-activity relationships (SAR) of peptide ligands with KOPr activity and to identify peptidic KOPr ligands with desirable pharmacological profiles for use in vivo. Three specific aims will be pursued to accomplish these goals: 1) To explore the SAR of novel analogs of the dynorphins, the endogenous ligands for KOPr, 2) to explore the SAR of novel KOPr peptides that are structurally unrelated to the dynorphins, and 3) to evaluate peptide KOPr ligands in vivo using mouse models of analgesia, antinociceptive tolerance, physiological responses and place conditioning. We hypothesize that peptide agonists with mixed agonist/KOPr antagonist activity will demonstrate significant antinociception with decreased liabilities. The insights from these studies will further enhance our understanding of the roles of KOPr in various pharmacological processes and advance the development of KOPr ligands with potential for therapeutic application. PUBLIC HEALTH RELEVANCE: While narcotic analgesics such as morphine have been used extensively to treat pain, their use has been limited by their serious side effects. Thus there is a need to identify promising lead compounds with improved side effect profiles that could result in improved treatment of pain. Compounds with mixed activity involving kappa opioid receptors may possess analgesic activity with fewer side effects, but the development of these mixed activity drugs has been limited. Antagonists blocking kappa opioid receptors may also have potential in the treatment of mood disorders and drug abuse. There is a clinical need for these agents, as described in this proposal that can be used as pharmacological tools and as lead compounds for further development.