Mixed Kappa-Mu Opioids: Synthesis and Evaluation

描述（由申请人提供）：这是一份竞争性续期申请，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kappa选择性激动剂相比，混合kappa/mu阿片类药物- cycloorphan及其n-环丁基甲基衍生物MCL-101在急性和慢性治疗中都能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kappa和mu受体的相对亲和力和有效性，我们提出了三种合成混合kappa/mu阿片样物质的创新方法：(1)用氨基噻唑生物等构取代阿片样物质中的苯酚部分合成吗啡；(2)二价吗啡的合成。将努力建立最佳的吗啡肽药效团；确定药效团上连接连接体的最佳位置；改变连接器的类型；并确定连杆的最优长度；(3)基于我们成功地对cycloorphan和MCL-101的n -烷基和3-羟基功能进行生物等构修饰，获得了对kappa/mu受体具有高亲和力的化合物，我们将进一步研究在环- c（环己基环）中引入官能团。我们拟合成的化合物包括：6-氨基/6-羟基吗啡酮；6-氧和8-氧吗啡酮；以及它们的类似物。

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.