PHARMACOLOGICAL CHARACTERIZATION OF ENDOGENOUS CANNABINOIDS

该项目的主要奋进是表征药理学 内源性大麻素的作用，并确定共同点， δ/9-THC和内源性大麻素之间的差异。 我们 建议继续进行结构-活性关系研究， 迄今为止产生了有效和稳定的大麻素类似物。我们打算 扩大这些SAR研究，以更好地了解花生四烯酸 与大麻素受体相互作用。类似物， 四氢大麻酚/大麻素混合物将提供更好的 了解它们共同的结构特征。我们 还计划制备2-花生四烯酸甘油的稳定和有效的类似物 这将大大提高我们的能力，充分表征其 药理学特性将对这些类似物进行CB 1和 CB 2受体亲和力，35/S-GTP γ S结合的活化， 小鼠四分体测定以及小鼠和大鼠药物辨别。我们将 我也在寻找新的线索，使CB 1的衍生物具有选择性， 拮抗剂SR 141716 A。毫无疑问，大麻素 与大麻素受体结合并产生类似的药理作用 与δ/9-THC的那些相比，它们的 药理学特征我们会进行研究，以确定 anandamide和delta 9-THC之间的这些差异是由于 药代动力学或药效学因素。将开展研究， 为了更清楚地定义大脑中大麻素水平 以及它所产生的药理作用， 用代谢抑制剂操纵其药理作用， 与效力的伴随变化相关。目前，它没有 似乎annandamide能够产生耐受性或 与delta/9-THC的依赖程度相同。几种不同的策略 将被用来确定花生四烯酸是否可以产生强大的 宽容对花生四烯酸酰胺产生耐受性的条件 将用于评估大麻素的依赖性。发展 依赖anandamide将表明内源性系统的作用 在成瘾性疾病中，而大麻素不能产生 依赖性将提供进一步的证据表明，THC和 anandamide是不相同的。开发稳定和有效的类似物 2-花生四烯酸甘油将使我们能够评估耐受性， 这种内源性配体的依赖性也是如此。一个附加 评估大麻素类THC性质的方法是使用 小鼠和大鼠的药物辨别。将尝试训练 动物接受更高和更低剂量的THC， 发现大麻素对四氢大麻酚样反应的可能性

The major endeavor of this project is to characterize the pharmacological actions of the endogenous cannabinoids and identify commonalities and differences between delta/9-THC and the endogenous cannabinoids. We propose to continue the structure-activity relationship studies that have thus far resulted in potent and stable anandamide analogs. We intend to expand these SAR studies to gain a better understanding of how anandamide interacts with cannabinoid receptors. Analogs that are tetrahydrocannabinol/anandamide hybrids will provide a better understanding of structural features that are common for both of them. We also plan to prepare stable and potent analogs of 2-arachidonyl-glycerol which will greatly enhance our ability to fully characterize its pharmacological properties. These analogs will be evaluated for CB1 and CB2 receptor affinity, activation of 35/S-GTPgammaS binding, potency in the mouse tetrad assay, and mouse and rat drug discrimination. We will also pursue new leads in making derivatives of the CB1 selective antagonist SR141716A. While there is no question that anandamide interacts with the cannabinoid receptor and produces pharmacological effects similar to those of delta/9-THC, there are several differences in their pharmacological profile. We will undertake studies to determine whether these differences between anandamide and delta9-THC are due to pharmacokinetic or pharmacodynamics factors. Studies will be carried out to more clearly define the relationship between brain levels of anandamide and pharmacological effects it produces and to determine whether manipulation of its pharmacological effects with metabolic inhibitors is associated with concomitant changes in potency. Presently, it does not appear that annandamide is capable of producing either tolerance or dependence to the same extent as delta/9-THC. Several different strategies will be employed to determine whether anandamide can produce robust tolerance. The conditions under which tolerance develops to anandamide will be used to assess the dependence liability of anandamide. Development of dependence by anandamide would suggest a role for the endogenous system in addictive disorders, whereas failure of anandamide to produce dependence would provide further evidence that the actions of THC and anandamide are not identical. The development of stable and potent analogs of 2-arachidonyl-glycerol will allow us to evaluate the tolerance and dependence liability of this endogenous ligand as well. One additional means of assessing the THC-like properties of anandamide is the use of drug discrimination in mice and rats. Attempts will be made to train animals to higher and lower doses of THC which will increase the likelihood of uncovering THC-like responding by anandamide.