EXOGENOUS AND ENDOGENOUS CANNABINOIDS--A COMPARISON

拟议研究的总体目的是比较以下结构- Delta-9主观效应的活动性关系 四氢大麻酚(Delta-9-THC)和其他具有 内源性大麻素受体配体的类似物(R-甲烷胺) 阿南达胺。化学结构与药物作用之间的相关性揭示 对某一特定药物效应或药物作用的结构要求。 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 这种关系还没有得到证明。来自我们自己和其他人的研究 实验室已经显示出合成的THC的类似性质 大麻素和大麻仿制药高度依赖于 结构配置。拟议的研究调查了潜在的 已知拟大麻化合物对R-的立体选择性 甲烷胺。这些研究还侧重于确定有用的 通过有效阻断大麻滥用的药物疗法 具有精神活性和大麻仿生性。本项目将 利用药物辨别程序与大鼠作为动物模型 评估Delta-9-THC，R-甲烷胺的精神活性， 以及相关化合物。毒品歧视是最常用的 研究毒品的主观、醉人效应的范式 临床前精神药理学。这项提议的一个特点是 使用不同训练剂量的THC产生不同的疗效 要求。此外，食物保持响应和开阔的田野 还将进行活动研究。通过提供重要的 内源性ANANDAME和外源性Delta-9的SAR信息 以及潜在的大麻仿制拮抗剂，这些研究将 不仅增加了我们对行为神经生物学的理解 大麻的滥用和依赖，但也可能导致发展 有效的药物治疗。

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 an analog (R-methanandamide) of the endogenous cannabinoid receptor ligand anandamide. 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 potential stereoselectivity of known cannabimimetic compounds with regard to R- methanandamide. 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.