Mixed Kappa-Mu Opioids: Synthesis and Evaluation

混合 Kappa-Mu 阿片类药物：合成与评价

基本信息

批准号：
7649440
负责人：
John L Neumeyer
金额：
$ 31.17万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
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/7649440
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

项目摘要

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）：这是一项竞争性续签应用，以继续综合和评估混合Kappa/MU阿片类药物，这可能对可卡因滥用和依赖性治疗可能有用。我们发现，混合Kappa/Mu阿片类药物及其N-环丁基甲基衍生物MCL-101均急性和慢性治疗，降低了可卡因自我给药剂量，而产生的副作用较少，而副作用较少。为了进一步延长Kappa和Mu受体的相对亲和力和功效，我们提出了三种创新方法，以合成混合Kappa/Mu阿片类药物：（1）形态学与aminothiazole生物疗法替代ePioiety in opioiets in Opioids contimotics sentations合成。（2）二价形态的合成。将努力建立最佳的吗啡药算术；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；（3）基于我们在旋风中的N-烷基和3-羟基功能的生物酶修饰的基础上，导致在Kappa/Mu受体中具有高亲和力的化合物，我们的进一步研究将针对Ring-c（环甲基己基环）引入功能组。我们建议制作的化合物包括：6-氨基/6-羟基形态； 6-oxa和8-oxa morphinans;和他们的类似物。新化合物的亲和力和选择性将使用对MU，Delta和Kappa阿片受体有选择性的放射性结合测定法确定。化合物对夫妇对G蛋白的功效将通过测量来自中国仓鼠卵巢（CHO）细胞的[35S] -GTPGAMMAS结合，这些细胞与人阿片类受体之一稳定转染。小鼠温水尾部轻弹和扭动测定将用于确定体内新化合物的效力和选择性。这些测定将导致化合物的药理特征的发展，这些化合物将有助于识别在临床前猴子研究中将是最佳候选者的化合物。拟议的研究将在两个独立地点进行。该药物合成成分将在约翰·诺梅耶（John L.