Mixed Kappa-Mu Opioids: Synthesis and Evaluation

混合 Kappa-Mu 阿片类药物：合成与评价

• 批准号: 7938268
• 负责人: John L Neumeyer
• 金额: $ 8.59万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938268
• 关键词: Acute; Adverse effects; Affinity; Agonist; Amides; Analgesics; Behavioral; Binding; Biological; Biological Assay; Biological Availability; Budgets; Carbon; Chinese Hamster; Chinese Hamster Ovary Cell; Chronic; Cocaine; Cocaine Abuse; Dependence; Development; Doctor of Philosophy; Dose; Drug abuse; Evaluation; GTP gamma S; GTP-Binding Proteins; Grant; Hospitals; Human; Hydroxyl Radical; Investigation; Length; Ligands; Macaca mulatta; Measures; Membrane; Metabolism; Modeling; Modification; Monkeys; Morphinans; Morphine; Mus; Opioid; Opioid Receptor; Ovary; Pharmaceutical Preparations; Pharmacotherapy; Phenols; Property; Relative (related person); Research; Schedule; Sedation procedure; Self Administration; Series; Site; Structure; Tail; Testing; Universities; Vomiting; Water; analog; base; cyclorphan; dimer; functional group; in vivo; innovation; kappa opioid receptors; mu opioid receptors; multidisciplinary; novel; novel strategies; pharmacophore; pre-clinical; preclinical evaluation; radioligand; saliva secretion; success; tool

DESCRIPTION (provided by applicant): This is a competing renewal application to continue the synthesis and evaluation of mixed kappa/mu opioids that may be useful for the treatment of cocaine abuse and dependence. We have found that both acute and chronic treatment with the mixed kappa/mu opioids - cyclorphan and its n-cyclobutylmethyl derivative, MCL-101, reduced cocaine self-administration dose-dependently and produced fewer side effects than kappa-selective agonists. In an effort to further extend the duration of action and to manipulate relative affinity and efficacy at kappa and mu receptors, we propose three innovative approaches to the synthesis of mixed kappa/mu opioids: (1) Synthesis of morphinans with aminothiazole bioisosteric substitution of the phenol moiety in opioids; (2) Synthesis of bivalent morphinans. Efforts will be directed to establish the optimum morphinan pharmacophores; determine the optimal site on the pharmacophore connecting the linkers; vary the type of linkers; and establish the optimal length of the linkers; and (3) Based on our success with the bioisosteric modifications of the N-alkyl and 3-hydroxyl functions of cyclorphan and MCL-101 that resulted in compounds with high affinity at kappa/mu receptors, our further investigation will be directed to the introduction of functional groups in the ring-C (cyclohexyl ring). The compounds we propose to make include: the 6-amino/6-hydroxyl morphinans; 6-oxa and 8-oxa morphinans; and their analogues. The affinity and selectivity of new compounds will be determined by using radioligand binding assays that are selective for mu, delta, and kappa opioid receptors. The efficacy of compounds to couple to G proteins will be determined by measuring [35S]-GTPgammaS binding to membranes from Chinese hamster ovary (CHO) cells that are stably transfected with one of the human opioid receptors. The mouse warm-water tail flick and writhing assays will be used to determine the potency and selectivity of new compounds in vivo. These assays will results in the development of pharmacological profiles of compounds that will assist in identifying compounds that will be the best candidates to test in the preclinical monkey studies. The proposed research will be conducted at two independent sites. The medication synthesis component will be conducted at the McLean Hospital under the direction of John L. Neumeyer, Ph.D., and the pharmacological evaluation component will be conducted at the University of Rochester under the direction of Jean M. Bidlack, Ph.D.

描述(由申请人提供)：这是一项竞争性的续展申请，目的是继续合成和评估可能有助于治疗可卡因滥用和依赖的kappa/u混合阿片类药物。我们发现，与kappa选择性激动剂相比，kappa/u阿片类药物-环诺芬及其N-环丁基甲基衍生物MCL-101的急性和慢性治疗均可剂量依赖性地减少可卡因的自我给药，并产生更少的副作用。为了进一步延长阿片类药物的作用时间，并调控kappa和mU受体的相对亲和力和药效，我们提出了三种合成kappa/mU混合阿片类药物的创新方法：(1)用氨基噻唑生物等位取代阿片类药物中的苯酚基团合成吗啡；(2)合成二价吗啡。我们将努力建立最佳的吗啡药效团；确定连接连接体的药效团上的最佳位置；不同类型的连接体；以及确定连接体的最佳长度；以及(3)在我们成功对环孤儿和MCL-101的N-烷基和3-羟基进行生物等位阻抗修饰从而产生在kappa/u受体上具有高亲和力的化合物的基础上，我们的进一步研究将针对在-C环(环己基环)中引入官能团。我们拟合成的化合物包括：6-氨基/6-羟基吗啡；6-氧和8-氧吗啡；以及它们的类似物。 新化合物的亲和力和选择性将通过对u、Delta和kappa阿片受体具有选择性的放射性配基结合分析来确定。化合物与G蛋白偶联的有效性将通过测量中国仓鼠卵巢(CHO)细胞膜上的[35S]-GTP GammaS结合来确定，中国仓鼠卵巢(CHO)细胞稳定地转染了一种人类阿片受体。小鼠温水甩尾和扭动试验将用于确定新化合物在体内的效力和选择性。这些分析将导致化合物的药理学特征的发展，这将有助于确定将是在临床前猴子研究中测试的最佳候选化合物。 拟议的研究将在两个独立的地点进行。药物合成部分将在McLean医院在John L.Neumeyer博士的指导下进行，药理评估部分将在罗切斯特大学在Jean M.Bidlack博士的指导下进行。