Exogenous/endogenous cannabinoids--A comparison

描述(由申请人提供)：我们在理解方面的最新进展 大麻素作用的神经化学/生理基础提供了令人兴奋的 继续努力进一步界定该机制的背景材料 拟大麻制剂的作用。大麻素和大麻仿制物诱导 它们通过调节四个受体中的一个或多个的功能而发挥作用 已知的“大麻素靶蛋白”：CB1、CB2、双胺酰胺酶和 阿南达奈德运输机。拟议研究的总体目的是 比较主观效应的结构-活性关系 Delta-9-四氢大麻酚(Delta-9-THC)和其他具有 类似物，如推定内源性的[(R)-甲烷胺]和AM-1346 大麻素受体配体ANANANDAME以及来自第二个 脑内发现内源性大麻素家族，即2-花生四烯甘油(2-AG)。 其他检查目标涉及负责合成的酶 和降解阿南达胺以及阿南达胺转运蛋白系统 内源性大麻素的再摄取。化学结构与药物的相关性研究 动作揭示了给定药物效果或药物的结构要求 行动。尽管一些研究表明，Delta-9-THC和双胺以及 (R)-甲烷胺有许多相似的性质，一对一的关系具有 没有被演示过。来自我们自己和其他实验室的研究表明 合成大麻素和大麻仿制品的类似THC特性是 高度依赖于特定的结构配置。建议进行的研究 研究ANANDAME-和2-AG类似物在 与已知的大麻仿制化合物进行比较。这些研究还侧重于 通过有效地阻止大麻滥用来确定有效的药物疗法 具有精神活性的、模仿大麻的特性。本项目将利用 以大鼠为动物模型的药物辨别程序 Delta-9-THC、(R)-甲烷胺及相关化合物的精神活性 化合物。毒品歧视是最常用的研究范式 临床前药物的主观、醉人效应 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，以创造不同的疗效需求。此外，食物 还将进行持续反应和公开实地活动研究。 通过提供关于内源性花生胺的SAR的重要信息和 外源Delta-9-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.