Exogenous/endogenous cannabinoids--A comparison

描述（由申请人提供）：我们了解的最近进展 大麻素作用的神经化学/生理学基础提供了令人兴奋的 继续努力进一步界定机制的背景材料 大麻模拟剂的作用。大麻素和拟大麻素诱导 通过调节一个或多个四个受体的功能， 已知的"大麻素靶蛋白"：CB 1、CB 2、大麻素酰胺酶，以及 anandarnide转运蛋白。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）和其他大麻模拟物， 类似物，如[（R）-methanandamide]和AM-1346， 大麻素受体配体大麻素酰胺以及来自第二种大麻素受体配体的代表 在大脑中发现的内源性大麻素家族，即，2-花生四烯甘油（2-AG）。 其他检查目标涉及负责合成的酶 和降解的花生四烯酸和花生四烯酸转运系统参与 内源性大麻素的再摄取。化学结构与药物的构效关系 作用揭示了给定药物作用或药物的结构要求 行动上尽管一些研究表明，δ-9-THC和大麻素以及 （R）-甲烷andamide具有许多相似的性质，一对一的关系， 没有被证明。我们和其他实验室的研究表明 合成大麻素和大麻模拟物的THC样性质是 高度依赖于特定的结构配置。拟议的研究 研究大麻素-和2-AG类似物在 与已知的拟大麻化合物的比较。这些研究还重点关注 通过有效阻断药物滥用， 精神刺激类大麻物质本项目将利用 用大鼠作为动物模型的药物鉴别程序， δ-9-THC、（R）-甲酰胺和相关物质的精神活性 化合物.药物歧视是最常用的研究范式 临床前药物的主观、致醉作用 精神药理学该提案的一个特点是使用不同的 训练剂量的THC以产生不同的功效需求。此外，食物 还将进行持续的应对和露天活动研究。 通过提供关于内源性大麻素的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 这些研究不仅会加深我们对行为神经生物学的理解， 大麻滥用和依赖，但也可能导致发展， 有效的药物治疗。

DESCRIPTION (provided by applicant): 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. Cannabinoids and cannabimimetics induce their receptor-based effects by modulating the functions of one or more of four known "cannabinoid target proteins": CB1, CB2, anandamide amidase, and the anandarnide transporter. The overall purpose of the proposed studies is to compare the structure-activity relationships of the subjective effects of delta-9-tetrahydrocannabinol (delta-9-THC) and other cannabimimetics with analogs such as [(R)-methanandamide] and AM-1346 of the putative endogenous cannabinoid receptor ligand anandamide as well as representatives from a second endocannabinoid family discovered in brain, i.e., 2-arachidonyiglycerol (2-AG). Other targets for examination concern the enzymes responsible for the synthesis and degradation of anandamide and the anandamide transporter system involved in reuptake of endocannabinoids. The SAR between chemical structure and drug action reveals the structural requirements for a given drug effect or drug action. Though some studies suggest that delta-9-THC and anandamide as well as (R)-methanandamide 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. The proposed studies investigate structural requirements of anandamide- and 2-AG analogs in comparison to known cannabimimetic compounds. These studies also focus on identifying useful pharmacotherapies for cannabis abuse by effectively blocking the psychoactive, cannabimimetic properties. The present project will utilize drug discrimination procedures with rats as an animal model for assessing the psychoactive properties of delta-9-THC, (R)-methanandamide, and related compounds. Drug discrimination is the most commonly used paradigm for studying the subjective, intoxicating effects of drugs in preclinical psychopharmacology. A special feature of this proposal is the use of different training doses of THC to create different efficacy demands. Additionally, food maintained responding and open-field activity studies will also be conducted. By providing important information on the SAR of endogenous anandamide and exogenous delta-9-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.