Mixed Kappa-Mu Opioids: Synthesis and Evaluation

混合 Kappa-Mu 阿片类药物：合成与评价

• 批准号: 7256996
• 负责人: John L Neumeyer
• 金额: $ 31.8万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256996
• 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; Personal Satisfaction; 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; 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）：这是一项竞争性续展申请，旨在继续合成和评价可能用于治疗可卡因滥用和依赖的混合kappa/mu阿片类药物。我们已经发现，用混合的κ/μ阿片类药物-环啡烷及其N-环丁基甲基衍生物MCL-101进行的急性和慢性治疗都以剂量依赖性方式减少了可卡因自我给药，并且产生的副作用比κ选择性激动剂少。为了进一步延长作用持续时间并操纵对κ和μ受体的相对亲和力和功效，我们提出了三种合成混合κ/μ阿片类药物的创新方法：（1）用氨基噻唑生物电子等排取代阿片类药物中的苯酚部分合成吗啡烷;（2）合成二价吗啡烷。将致力于建立最佳吗啡喃药效团;确定连接接头的药效团上的最佳位点;改变接头的类型;并建立接头的最佳长度;和（3）基于我们成功地对环啡烷和MCL-101的N-烷基和3-羟基官能团进行生物电子等排修饰，得到了对κ/μ受体具有高亲和力的化合物，我们的进一步研究将针对在环-C（环己基环）中引入官能团。我们建议制备的化合物包括：6-氨基/6-羟基吗啡喃; 6-氧杂和8-氧杂吗啡喃;及其类似物。 新化合物的亲和力和选择性将通过使用对μ、δ和κ阿片受体具有选择性的放射性配体结合测定来确定。化合物与G蛋白偶联的效力将通过测量[35 S]-GTP γ S与来自中国仓鼠卵巢（CHO）细胞的膜的结合来确定，所述细胞用人阿片样物质受体之一稳定转染。小鼠温水甩尾和扭体试验将用于确定新化合物的体内效力和选择性。这些试验将导致化合物药理学特征的开发，这将有助于鉴定在临床前猴研究中检测的最佳候选化合物。 拟议的研究将在两个独立的地点进行。药物合成部分将在姆克林医院在John L. Neumeyer博士，药理学评价部分将在Jean M.的指导下在罗切斯特大学进行。Bidlack博士