EXOGENOUS/ENDOGENOUS CANNABINOIDS--CHEMISTRY & BEHAVIOR

该提案要求建立一个RSDA， 正在进行的关于大麻素和相关化合物的研究。 的 最近的进展，我们的理解神经化学/生理 大麻素作用的基础提供了令人兴奋的背景材料， 继续努力进一步阐明 大麻模拟剂。拟议研究的总体目的是 比较主观效应的构效关系， δ 9-四氢大麻酚（δ 9-THC）和内源性大麻素 受体配体花生四烯酸化学结构与药物的构效关系 作用揭示了立体选择性的结构要求， 特定药物作用或药物作用的立体特异性。尽管一些 研究表明，delta 9-THC和anandamide有许多相似之处， 属性，一对一的关系尚未得到证明。研究 我们自己和其他实验室的研究表明， 合成大麻素和拟大麻素高度依赖于 特殊的结构配置。总的来说，这些研究表明， 大麻模拟活性是立体选择性的，即，是否 化合物是（+）-或（-）-对映异构体，甲基平面性， 以环己烷环和侧链为特征。职业 提出的研究调查，潜在的立体选择性已知的 大麻素类似物化合物。这些研究还 重点是查明对大麻滥用有用的药物疗法， 有效地阻断了刺激精神的大麻类物质虽然 已经鉴定出许多化合物具有大麻模拟物 有效阻断或拮抗THC线索的化合物 尚未被隔离。本项目将主要利用 用大鼠作为评估的动物模型的药物辨别程序 delta 9-THC、大麻素的精神活性和相关试验 化合物.毒品歧视是最常用的范例， 在临床前研究药物的主观、致醉作用， 精神药理学本提案的目的将在 一系列4个主要实验，需要5年时间才能完全完成。的 总体目的是：l）确定δ 9-THC和anadamide的SAR是否 在主观辨别刺激属性方面是相似的， 和2）探索拮抗大麻模拟作用的潜力。通过 提供关于内源性花生四烯酸异戊酰胺的SAR的重要信息， 外源性δ 9-THC，以及潜在的大麻模拟物拮抗剂， 这些研究不仅会增加我们对行为的理解， 大麻滥用和依赖的神经生物学，但也可能导致 开发有效的药物治疗。批准本 该提案将创造金融稳定，并确保上述目标 可以满足。

This proposal is a request for a RSDA which would facilitate and extend ongoing research concerning cannabinoids and related compounds. The recent advances in our understanding of the neurochemical/physiological basis of cannabinoid action provide exciting background material for continuing efforts to further delineate the mechanism of action of cannabimimetic agents. The overall purpose of the proposed studied 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 pro posed 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 5 years for full completion. The overall purpose is to: l) 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. Approval of this proposal would create financial stability and ensure that the above goals can be met.