Exogenous/endogenous cannabinoids--Chemistry & behavior

描述：（申请人提供） 这个建议是一个伊萨（K 02）的要求，这将加强我的研究 职业发展和扩大正在进行的研究有关大麻和 相关化合物。最近我们在了解 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。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）和其他具有 内源性大麻素受体配体的类似物[（R）-甲雄酰胺] 花生四烯酸化学结构和药物作用之间的SAR揭示了 特定药物效果或药物作用的结构要求。尽管一些 研究表明，δ-9-THC和大麻素以及（R）-甲基大麻素 共享许多相似的属性，一对一的关系并没有 演示。我们自己和其他实验室的研究表明， 合成大麻素和大麻模拟物的THC样性质是高度依赖的。 取决于特定的结构配置。拟议的研究 研究已知拟大麻化合物潜在立体选择性 关于（R）-甲烷andamide。这些研究还侧重于确定有用的 通过有效阻断精神活性物质， 大麻模拟物性质。本项目将利用药物歧视 用大鼠作为动物模型评估精神活性物质的方法 δ-9-THC、（R）-甲酰胺和相关化合物的性质。药物 辨别是研究主观的最常用的范例， 临床前精神药理学中药物的致醉作用。一个特殊 该建议的特点是使用不同的THC训练剂量， 创造不同的功效需求。此外，食物保持反应， 还将进行野外活动研究。通过提供重要的 内源性大麻素和外源性δ-9-THC的SAR信息， 以及潜在的大麻模拟拮抗剂，这些研究不仅将增加 我们对大麻滥用的行为神经生物学的理解， 依赖，但也可能导致有效的药理学的发展， 治疗。

DESCRIPTION: (provided by applicant) This proposal is a request for an ISA (K02) which would enhance my research career development and extend ongoing research concerning cannabioids 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 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.