Endogenous/exogenous cannabinoids: A comparison

描述（由申请人提供）：自从发现大麻中主要活性成分9-四氢大麻酚（THC）等化学物质的特异性识别位点（受体）以来，大麻素的研究取得了巨大进展。内源性大麻素信号系统（ECS）因此可能作为大麻“高”的生物基质。这种主观状态可能是人类大麻消费的基础，可能导致强迫性大麻摄入和依赖性障碍。药物辨别是用于评估动物（和人）中“主观”经历的药物效应的强大的、非选择性模型，并且是该应用中的主要体内行为技术。大麻素受体CB 1（CB 1 R）激动剂和拮抗剂将使用不同剂量进行药物辨别训练，提供具有不同灵敏度水平的体内试验。这是补充观察性研究和时间表控制的反应，允许在配体的深入表征。这项研究的一个主要目的是确定新的药物，将转化为更好的药物疗法，以打击大麻成瘾。减轻 身体依赖个体的戒断相关效应可能是成瘾过程中的一个重要动机因素。新分子由现场专业人员设计和合成。一个焦点是鉴定和改进体内中性CB 1 R拮抗剂。目前大多数CB 1 R拮抗剂还显示内在活性（反向激动作用），可能会妨碍患者在治疗环境中的依从性。因此，这些研究将扩大我们对ECS的理解，ECS由两种主要的内源性信号分子花生四烯酸酰胺（AEA）和2-花生四烯酸甘油（2-AG）组成，作用于两种已知的受体CB 1和CB 2，在正常的身体功能和病理生理学中。本申请的另外的“治疗”靶标涉及选择性地影响参与内源性大麻素失活的酶的配体，从而潜在地避免直接受体活化。行为研究得到了合作教师在追求这些目标时提供的神经/生物化学程序的帮助。除了AEA之外，关于2-AG的最新进展允许对ECS信号传导中的这种主要内源性大麻素有更全面的了解。通过获得内源性物质功能的信息，（AEA和2-AG）和外源性THC以及体内中性阻断剂，这些研究不仅将进一步加深我们对大麻滥用/依赖的行为神经生物学中ECS信号传导的理解，而且还可能导致开发用于治疗涉及大麻/大麻的疾病的有效药物，和“类似四氢大麻酚的设计师”大麻仿制药。

DESCRIPTION (provided by applicant): Research on cannabinoids has progressed tremendously since the discovery of specific recognition sites (receptors) for chemicals like ¿9-tetrahydrocannabinol (THC), the main active ingredient in marijuana. The endocannabinoid signaling system (ECS) thus likely serves as the biological substrate for the marijuana "high". This subjective state presumably underlies human marijuana consumption that may lead to compulsive cannabis intake and dependence disorders. Drug discrimination is a powerful, pharmacologically selective model for assessing "subjectively" experienced drug effects in animals (and man) and is the major in vivo behavioral technique in this application. Cannabinoid receptor CB1 (CB1R) agonists and antagonists will be trained in drug discrimination using different doses, providing for in vivo assays with different sensitivity levels. This is complemented by observational studies and schedule controlled responding allowing for an in depth characterization of ligands. A major aim of this research is to identify new medications that will translate into better pharmacotherapies for combating marijuana addiction. Alleviation of withdrawal-related effects in physically dependent individuals likely is an important motivational factor in addiction processes. New molecules are designed and synthesized by on site expertise. One focus is to identify and refine in vivo neutral CB1R antagonists. Most current CB1R antagonists also display intrinsic activity (inverse agonism) that may hamper patient compliance in treatment settings. Thus, the studies will expand our understanding of the ECS, comprised of two major endogenous signaling molecules, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) acting on two known receptors, CB1 and CB2, in normal body function and pathophysiology. Additional "therapeutic" targets for the application concern ligands selectively affecting the enzymes involved in the deactivation of the endocannabinoids, thus potentially avoiding direct receptor activation. The behavioral studies are aided by neuro/biochemical procedures provided by collaborating faculty in pursuing these goals. In addition to AEA, recent developments regarding 2-AG allow for a much more comprehensive understanding of this major endocannabinoid in ECS signaling. By obtaining information on the functions of the endogenous substances (AEA and 2-AG) and the exogenous THC, as well as in vivo neutral blocking agents, these studies will not only further our understanding of ECS signaling in the behavioral neurobiology of cannabis abuse / dependence, but may also lead to the development of effective medications for treating disorders involving cannabis / marijuana, and "designer THC-like" cannabimimetics.