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：
8334518
负责人：
John L Neumeyer
金额：
$ 37.15万
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 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334518
关键词：
Acute Adverse effects Affinity Agonist Alcohol abuse Alcohols Antidepressive Agents Attenuated Behavioral Binding Biological Biological Assay Brain Budgets Chinese Hamster Ovary Cell Chronic Clinical Trials Cocaine Cocaine Abuse Cocaine Dependence Contractor Convulsants Dependence Development Doctor of Philosophy Dopamine Agonists Dopamine Receptor Dose Drug abuse Evaluation GTP-Binding Proteins Grant Heroin Hospitals Human Hydroxyl Radical Investigation Ligands Macaca mulatta Measures Membrane Modification Monkeys Morphinans Morphine Mus Opiate Addiction Opioid Opioid Receptor Pattern Personal Communication Pharmaceutical Preparations Pharmacotherapy Phenols Public Health Rattus Relative (related person)Research Schedule Sedation procedure Self Administration Series Site Structure Tail Testing Time Universities Vomiting Water analog base cyclorphan functional group in vivo inhibitor/antagonist innovation kappa opioid receptors multidisciplinary novel novel strategies opioid abuse pre-clinical radioligand receptor receptor coupling reuptake saliva secretion success tool

项目摘要

DESCRIPTION (provided by applicant): This is a competing revised renewal application to continue the syntheses 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 k/¿ opioids - cyclorphan and butorphan (MCL-101) reduced cocaine self-administration dose-dependently and produced fewer side effects than k-selective agonists. In an effort to further extend the duration of action and to manipulate relative affinity and efficacy k and ¿ receptors, we propose innovative approaches to the synthesis of mixed k/¿ opioids. (1) Synthesis of morphinans with aminothiazole substitution of the phenol moiety in opioids. (2) 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 and selectivity at k/¿ receptors, our further investigation will be directed to the introduction of functional groups in the ring-C (cyclohexyl ring), and the synthesis of 3-amino- and 6-aminomorphinans. (3) 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. (4) The efficacy of compounds to couple to G proteins will be determined by measuring [35S]GTPgS binding to membranes from Chinese hamster ovary (CHO) cells that are stably transfected with one of the human opioid receptors. (5) The mouse warm-water tail flick and writhing assays will be used to determine the potency and selectivity of new compounds in vivo. (6) Determine the dose-effect time course functions of selected compounds on basal and cocaine- potentiated brain stimulation using intracranial-stimulation (ICSS). These assays will result in the development of pharmacological profiles of compounds that will assist in identifying compounds that will be the best candidates to test in preclinical monkey studies that could be carried out at McLean Hospital under a separate grant. The proposed research will be conducted at two independent sites. The synthesis component and the intracranial-stimulation studies (ICSS) will be conducted at McLean Hospital under the direction of John L. Neumeyer, Ph.D. and Elena Chartoff, 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（由应用程序提供）：这是一项竞争性修订的续订应用程序，可继续合成和评估混合的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，用混合的K/»绿色蛋白和慢性治疗 - 环形和Butorphan（MCL-101）降低了可卡因自我给药剂量的依赖性剂量，而副作用比K-选择性激动剂产生的副作用更少。为了进一步延长作用的持续时间并操纵相对亲和力K和受体，我们提出了与混合k/»o o o o o o o o o o o o o o o o o o o o o o o o o o的创新方法。（1）形成剂与胺基苯二唑替代苯酚部分中的合成。 (2) Based on our success with the bioisosteric modifications of the N-alkyl and 3-hydroxyl functions of cycloprhan and MCL-101 that resulted in compounds with high affinity and selectivity at k/¿ receptors, our further investigation will be directed to the introduction of functional groups in the ring-C (cyclohexyl ring), and the synthesis of 3-amino- and 6-aminomorphinans. （3）新化合物的亲和力和选择性将通过使用对MU，Delta和Kappa阿片受体有选择性的放射性结合测定法确定。（4）通过测量[35S] GTPG与中国仓鼠卵巢（CHO）细胞结合的[35S] GTPG的[35S] GTPG的效率，这些GTPG被稳定地与人阿片类药物受体稳定翻译而来。（5）小鼠温水尾部轻弹和写作测定法将用于确定体内新化合物的效力和选择性。（6）使用颅内刺激（ICS）确定所选化合物在碱性和可卡因训练脑刺激上的剂量效应时间过程。这些测定将导致化合物的药物概况的发展，这些化合物将有助于识别化合物，这些化合物将成为临床前猴子研究中测试的最佳候选者，这些候选者可以在麦克莱恩医院进行的单独赠款进行。拟议的研究将在两个独立地点进行。合成成分和颅内刺激研究（ICS）将在麦克莱恩医院（John L.以及Elena Chartoff博士，并将在Jean M. Bidlack博士的指导下在罗切斯特大学进行药理学评估部分。