Mixed Kappa-Mu Opioids: Synthesis and Evaluation

描述（由申请人提供）：这是一份竞争性的修订更新申请，旨在继续合成和评估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，与k-选择性激动剂相比，使用混合k/ o阿片类药物-旋克芬和布托芬（MCL-101）进行急性和慢性治疗均可减少可卡因的自我给药剂量依赖性，并且产生的副作用更少。为了进一步延长作用时间，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酚部分合成吗啡酮。(2)基于我们成功地对环孤儿和MCL-101的n -烷基和3-羟基进行生物等构修饰，获得了对k/¿受体具有高亲和力和选择性的化合物，我们将进一步研究在环- c（环己基环）中引入官能团，以及合成3-氨基和6-氨基氨基氨基酸。(3)新化合物的亲和力和选择性将通过对mu， delta和kappa阿片受体选择性的放射配体结合测定来确定。(4)在稳定转染一种人类阿片受体后，通过测定[35S]GTPgS与中国仓鼠卵巢（CHO）细胞膜的结合来确定化合物与G蛋白的偶联效果。(5)小鼠温水甩尾和扭尾实验将用于确定新化合物在体内的效价和选择性。(6)采用脑内刺激（ICSS）确定选定化合物对基础和可卡因增强脑刺激（ICSS）的剂量效应时程函数。这些分析将导致化合物的药理学特征的发展，这将有助于确定化合物，这些化合物将成为临床前猴子研究的最佳候选物，这些研究可以在麦克林医院进行，并获得单独的资助。拟议的研究将在两个独立的地点进行。合成部分和脑内刺激研究（ICSS）将在麦克林医院进行，由John L. Neumeyer博士和Elena Chartoff博士指导，药理学评估部分将在罗切斯特大学进行，由Jean M. Bidlack博士指导。

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.