Mixed Kappa-Mu Opioids: Synthesis and Evaluation

说明(由申请人提供)：这是一份竞争性修订的续展申请，目的是继续合成和评估可能有助于治疗可卡因滥用和依赖的kappa/u混合阿片类药物。我们发现，与k-选择性激动剂相比，使用k/？阿片类药物-环磷酰胺和丁托芬(MCL-101)的急性和慢性治疗均可剂量依赖性地减少可卡因的自我给药，并产生更少的副作用。为了进一步延长作用时间和控制k和？受体的相对亲和力和有效性，我们提出了合成混合k/？阿片类药物的创新方法。(1)阿片类药物中苯酚部分的氨基噻唑取代合成吗啡。(2)在我们对环己烷和MCL-101的N-烷基和3-羟基进行生物等位构型修饰的基础上，我们将进一步研究在-C环(环己环)上引入官能团，合成3-氨基和6-氨基吗啉。(3)新化合物的亲和力和选择性将通过对Mu、Delta和kappa阿片受体具有选择性的放射性配基结合分析来确定。(4)化合物与G蛋白偶联的有效性将通过测量稳定转染人阿片受体之一的中国仓鼠卵巢(CHO)细胞膜上的[35S]GTPgS结合来确定。(5)采用小鼠温水甩尾法和扭体法测定新化合物的体内活性和选择性。(6)测定所选化合物对基础脑刺激和可卡因增强脑刺激(ICSS)的量效时程功能。这些分析将产生化合物的药理学特征，帮助确定哪些化合物将是在临床前猴子研究中测试的最佳候选化合物，这些研究可以在麦克莱恩医院单独拨款下进行。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McLean医院在John L.Neumeyer博士和Elena Chartoff博士的指导下进行，药理评估部分将在罗切斯特大学在Jean M.Bidlack博士的指导下进行。

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.