PHARMACOLOGICAL CHARACTERIZATION OF ENDOGENOUS CANNABINOIDS

近年来，在药理学、生物化学和分子生物学方面的研究进展 大麻素使得探索其作用机制成为可能 这是以前没有的。的表征和克隆 大脑和周围的大麻素受体导致了成功的 内源性大麻素anandamide的鉴定。而且 现在证明了一个家族的内源性配体，而不是一个单一的 实体该项目的主要奋进是描述 内源性大麻素的药理作用及鉴定 delta 9-THC和内源性大麻素之间的共同点。新 将评估发现的内源性配体的药理学活性， 使用CB 1和CB 2受体结合、小鼠行为模型和 毒品歧视还将在小鼠中进行研究，以确定 对内源性配体产生耐受性的程度。交叉- 耐受性将使我们能够验证内源性配体和 Δ 9-THC份额。直到最近， 赛诺菲的研究小组宣布他们已经开发出 SR 141716 A，大麻素拮抗剂。因为我们的初步研究显示 这种化合物在拮抗和逆转 delta 9-THC的影响，我们相信它将发挥重要作用， 内源性配体的表征。由于事实上， 关于这种拮抗剂知之甚少， 将被确定。我们将生成delta 9-THC的pA 2值， 内源性配体，以确定哪些作用是通过 共同受体根据我们以往的经验，我们知道， 对合成大麻素类似物的耐受性发展可导致 受体下调和受体mRNA水平增加。因此，我们将 确定内源性配体是否能够改变这些 系统以类似的方式。 建议进行研究，以确定是否 拮抗剂自身表现出任何药理学作用， 对这些效应产生耐受性，以及受体上调和 mRNA水平的降低是由于长期给药。最后， 将对类似物进行构效关系研究， 内源性配体和拮抗剂。到目前为止，我们还没有一个明确的 了解受体-配体相互作用， 激动剂如THC和花生四烯酸衍生物结构多样。 更重要的是，我们不知道 SR 141716 A，这是其拮抗特性的原因。的结果 我们的研究将为其他成员国提供有益的探索和指导 的项目计划。

Recent advances in pharmacological, biochemical and molecular aspects of cannabinoids make it possible to explore the mechanism of actions in ways which were not available before. Characterization and cloning of cannabinoid receptors in brain and periphery led to the successful identification of the endogenous cannabinoid anandamide. Moreover, there is now evidence for a family of endogenous ligands rather than a single entity. The major endeavor of this project is to characterize the pharmacological actions of the endogenous cannabinoids and identify commonalties between delta9-THC and the endogenous cannabinoids. Newly discovered endogenous ligands will be assessed for their pharmacological profile using CB1 and CB2 receptor binding, a mouse behavioral model and drug discrimination. Studies will also be conducted in mice to determine the degree to which tolerance develops to the endogenous ligands. Cross- tolerance will allow us to verify which actions the endogenous ligands and delta9-THC share. An antagonist has not been available until the recent announcement by the research group at Sanofi that they had developed SR141716A, a cannabinoid antagonist. Since our preliminary studies show that this compound is effective in both antagonizing and reversing the effects of delta9-THC, we are confident that it will play a vital role in the characterization of endogenous ligands. Due to the fact that very little is known regarding this antagonist, a complete antagonistic profile will be determined. We will generate pA2 values for delta9-THC and the endogenous ligands to ascertain which actions are mediated through a common receptor. Based upon our previous experience, we know that tolerance development to synthetic cannabinoid analogs can result in receptor down-regulation and increased receptor mRNA levels. Thus, we will determine whether the endogenous ligands are capable of altering these systems in a similar fashion. Studies are proposed to determine whether the antagonist exhibits any pharmacological effects on its own, whether tolerance develops to these effects and whether receptor upregulation and decreased mRNA levels result from chronic administration. Finally, structure-activity relationship studies will be carried out for analogs of the endogenous ligands and the antagonist. As yet, we do not have a clear understanding of the receptor-ligand interactions which can accommodate agonists as structurally diverse as THC and arachidonic acid derivatives. Even more importantly, we do not know the structural properties of SR141716A which account for its antagonistic properties. The results from our studies will provide probes and valuable guidance to the other members of the Program Project.