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重度疼痛的重要药物，但由于耐受性、呼吸抑制等严重副作用和药物滥用的可能性，其使用受到限制。因此，有相当大的兴趣，以确定镇痛药减少负债的临床使用。κ阿片受体（KOPr）配体在疼痛的治疗中显示出治疗价值，并且还具有治疗情绪障碍和药物滥用的潜力。因此，探索KOPr活性的结构要求对于开发作为潜在新药的KOPr配体是重要的。拟议的研究集中在KOPr的肽配体上，这些肽配体还没有像其他阿片受体的肽那样被广泛研究。我们实验室最近的研究已经成功地鉴定了许多具有独特药理学特征的KOPr肽配体，这些肽配体与当前的KOPr配体相比具有明显的优势，包括一些在体内具有强效抗伤害活性的肽配体。因此，在这种竞争性更新申请中提出的研究的目标是继续我们对在KOPr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价肽在体内的阿片活性。本研究的长期目标是探索具有KOPr活性的肽配体的结构-活性关系（SAR），并鉴定具有用于体内的理想药理学特征的肽KOPr配体。将追求三个具体目标来实现这些目标：1）探索强啡肽的新类似物（KOPr的内源性配体）的SAR，2）探索结构上与强啡肽无关的新KOPr肽的SAR，和3）使用镇痛、抗伤害感受耐受、生理反应和位置调节的小鼠模型在体内评价肽KOPr配体。我们假设具有混合激动剂/KOPr拮抗剂活性的肽激动剂将表现出显著的抗伤害感受作用，并降低了责任。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.