EXOGENOUS AND ENDOGENOUS CANNABINOIDS--A COMPARISON

拟议研究的总体目的是比较以下结构- Delta9-主观效应的活动性关系 四氢大麻酚与内源性大麻素受体 配体脱氧核糖胺。化学结构与药物作用的相关性研究 揭示了立体选择性的结构要求或 特定药物效应或药物作用的立体特异性。尽管有些人 研究表明，Delta9-THC和阿南达胺有许多相似之处 属性，但尚未演示一对一的关系。研究 从我们自己的实验室和其他实验室已经显示出类似THC的特性 合成大麻素和大麻仿制药高度依赖于 特殊的结构配置。总的来说，这些研究表明 这种模仿大麻的活性是立体选择性的，即 化合物是(+)-或(-)-对映体，关于甲基平面性 到环己烷环，以及侧链的特性。这个 拟议的研究调查已知的潜在立体选择性 关于阿南达胺的拟大麻化合物。这些研究还包括 侧重于通过以下方式确定有效的大麻滥用药物疗法 有效地阻断了具有精神活性的、拟大麻的特性。尽管 许多化合物已被鉴定出具有大麻仿生性 有效阻断或拮抗THC线索的性质、化合物 还没有被隔离。本项目将主要利用 以大鼠为评价动物模型的药物鉴别程序 Delta9-THC、阿南达胺的精神活性及相关测验 化合物。毒品歧视是最常用的 临床前期药物的主观、醉人效应研究 精神药理学。这项提案的目标将在一份 一系列4个主要实验，需要4年时间才能完成。整体而言 目的是：1)确定Delta9-THC和阿那达胺的SAR是否 类似于主观区别刺激属性，以及 2)探索拟大麻效应的拮抗潜力。通过 提供了关于内源性花生胺和内源花青胺的SAR的重要信息 外源Delta9-THC，以及潜在的拟大麻拮抗剂， 这些研究不仅将增加我们对行为的理解 神经生物学对大麻的滥用和依赖，但也可能导致 开发有效的药物治疗方法。

The overall purpose of the proposed studies is to compare the structure- activity relationships of the subjective effects of delta9- tetrahydrocannabinol (delta9-THC) and the endogenous cannabinoid receptor ligand anandamide. The SAR between chemical structure and drug action reveals the structural requirements for the stereoselectivity or stereospecificity of a given drug effect or drug action. Though some studies suggest that delta9-ThC and anandamide share many similar properties, a one-on-one relationship has not been demonstrated. Studies from our own and other laboratories have shown the ThC-like properties of synthetic cannabinoids and cannabimimetics are highly dependent on particular structural configurations. In general, these studies suggest that cannabimimetic activity is stereoselective, i.e., whether the compound is a (+ )- or (-)-enantiomer, methyl group planarity with regard to the cyclohexane ring, and characteristics of the side chain. The proposed studies investigate potential stereoselectivity of known cannabimimetic compounds with regard to anandamide. These studies also focus on identifying useful pharmacotherapies for cannabis abuse by effectively blocking the psychoactive, cannabimimetic properties. Though a number of compounds have been identified that have cannabimimetic properties, compounds that effectively block or antagonize the THC cue have not yet been isolated. The present project will primarily utilize drug discrimination procedures with rats as an animal model for assessing the psychoactive properties of delta9-ThC, anandamide, and related test compounds. Drug discrimination is the most commonly used paradigm for studying the subjective, intoxicating effects of drugs in preclinical psychopharmacology. The Aims of this proposal will be addressed in a series of 4 main experiments, requiring 4 years to complete. The overall purpose is to: 1) determine if the SAR of delta9-THC and anadamide are similar with regard to subjective discriminative stimulus properties, and 2) explore the potential for antagonism of cannabimimetic effects. By providing important information on the SAR of endogenous anandamide and exogenous delta9-ThC, as well as potential cannabimimetic antagonists, these studies will not only add to our understanding of the behavioral neurobiology of cannabis abuse and dependence, but may also lead to the development of effective pharmacological treatments.