Mixed Kappa-Mu Opioids: Synthesis and Evaluation

描述（由申请人提供）：这是一项竞争性修订后的延续申请，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。我们发现，用混合的k/？阿片类药物-环啡烷和布托啡烷（MCL-101）进行急性和慢性治疗，可剂量依赖性地减少可卡因自我给药，并且产生的副作用比k-选择性激动剂少。为了进一步延长作用的持续时间并操纵K和<$受体的相对亲和力和功效，我们提出了合成混合K/<$阿片类药物的创新方法。(1)用氨基噻唑取代阿片类药物中的酚部分合成吗啡喃。(2)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，从而产生对k/μ受体具有高亲和力和选择性的化合物，我们的进一步研究将针对在环C（环己基环）中引入官能团，以及合成3-氨基-和6-氨基吗啡烷。(3)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。(4)化合物与G蛋白偶联的效力将通过测量[35 S]GTPgS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。(5)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。(6)使用颅内刺激（ICSS）确定所选化合物对基础和可卡因增强脑刺激的剂量效应时间过程函数。这些试验将导致化合物的药理学特征的开发，这将有助于确定化合物，这些化合物将是临床前猴研究中测试的最佳候选化合物，这些研究可以在姆克林医院根据单独的资助进行。拟议的研究将在两个独立的地点进行。合成部分和颅内刺激研究（ICSS）将在姆克林医院在John L. Neumeyer博士和埃琳娜·查托夫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

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.