Peptidic Ligands for Kappa Opioid Receptors

描述（由申请人提供）：虽然吗啡等麻醉性镇痛药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，有相当大的兴趣在确定镇痛药与减少责任的临床使用。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。本文的研究重点是KOPr的肽配体，这一研究还没有像其他阿片受体的肽那样广泛。我们实验室最近的研究已经成功地鉴定了一些KOPr肽配体，它们具有独特的药理学特征，比现有的KOPr配体具有明显的优势，包括一些在体内具有有效的抗伤害活性。因此，在这一竞争性更新申请中提出的研究目标是继续我们在KOPr中具有活性的关键肽配体的结构研究，并将这些研究扩展到包括评估体内阿片样物质活性的肽。本研究的长期目标是探索肽配体与KOPr活性的构效关系（SAR），并确定具有理想药理特征的肽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)探索动力啡肽的新型类似物，KOPr的内源性配体的SAR； 2)探索与动力啡肽结构无关的新型KOPr肽的SAR； 3)通过小鼠镇痛、抗伤害耐受性、生理反应和位置条件作用模型来评估肽KOPr配体在体内的作用。我们假设具有混合激动剂/KOPr拮抗剂活性的肽激动剂将显示出显著的抗伤害作用，并降低了负性。这些研究的见解将进一步增强我们对KOPr在各种药理学过程中的作用的理解，并推进具有治疗应用潜力的KOPr配体的开发。

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.