DEVELOPMENT OF SELECTIVE OPIOID ANTAGONISTS

本申请的目标是开发用于以下的生物化学探针： 更好地理解生物化学和分子机制 止痛药成瘾戒断的症状 具体目标包括：（1） 一类基于N-取代的阿片受体拮抗剂的开发 反式-3，4-二甲基-4-（3-羟基苯基）-哌啶类化合物的设计 基于上述模型的目标化合物;和（3）受体结合 目标化合物的评价，旨在确定选择性 μ、δ、κ 1、κ 2b阿片受体。 显示δ的化合物 选择性将在抗伤害感受性测定中评价， δ 2选择性。 将对选定的化合物进行厌恶和 在条件性位置偏好测定中增强特性。 在 此外，在任何浓度下Ki值小于100 nM的化合物， 阿片受体将提交给CPDD测试计划， NIDA药物发现计划。 为了实现上述目标，RTI在齐默尔曼博士的帮助下， (Eli礼来公司），将设计和合成目标化合物。 宝贵 起始物料也将由Eli Lilly提供。 罗斯曼医生 （NIDA-ARC）、Porreca（亚利桑那大学）和Shippenberg（NIDA-ARC） 将提供受体结合，镇痛，和行为 研究，分别。 目前，很少有有效的、系统活性的和选择性的非肽类化合物， 拮抗剂是可用的。 新的选择性合成 非肽类阿片受体拮抗剂将提供急需的 促进我们对阿片类药物作用的理解的工具 受体/内啡肽系统在正常和各种疾病状态中， 包括毒瘾 特别是，我们建议发展 选择性δ和κ拮抗剂可能提供新一代的 重要的研究药物和可能的治疗药物 患有毒瘾

The goal of this application is to develop biochemical probes for use in gaining a better understanding of biochemical and molecular mechanisms of analgesic addiction withdrawal. The specific objectives include: (1) the development of a class of opioid antagonists based on N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)-piperidines; (2) the design of target compounds based on the above model; and (3) the receptor binding evaluation of the target compounds designed to determine selectivity for mu, delta, kappa1, kappa2b opioid receptors. Compounds that show delta selectivity will be evaluated in antinociceptive assays for delta1 and delta2 selectivity. Selected compounds will be tested for aversive and reinforcing properties in the conditioned-place preference assays. In addition, compounds which have Ki values less than 100 nM at any of the opioid receptors will be submitted to the CPDD testing program and the NIDA Drug Discovery Program. In order to accomplish the goals above, RTI, with help from Dr. Zimmerman (Eli Lilly), will design and synthesize the target compounds. Valuable starting materials will also be provided by Eli Lilly. Drs. Rothman (NIDA-ARC), Porreca (University of Arizona), and Shippenberg )NIDA-ARC) will provide the receptor binding, antinicociceptive, and behavioral studies, respectively. At present, few potent, systematically active and selective nonpeptide antagonists are available. The design and synthesis of novel selective nonpeptide opioid receptor antagonists will provide critically needed tools to advance our understanding of the role of the opioid receptor/endorphin system in both normal and various disease states, including drug addiction. In particular, we propose that the development of selective delta and kappa antagonists may provide a new generation of important investigational drugs and possible treatment drugs for people suffering from drug addiction.