PHARMACOLOGICAL CHARACTERIZATION OF ENDOGENOUS CANNABINOIDS

本项目的主要工作是对药理作用进行表征。 内源性大麻素的作用，并确定共性和 Delta/9-THC与内源性大麻素的差异。我们 建议继续进行已有的结构-活性关系研究 到目前为止，得到了有效和稳定的烷基酰胺类似物。我们打算 扩大这些SAR研究，以更好地了解安非他明是如何 与大麻素受体相互作用。类比是 四氢大麻酚/安非他明杂交物将提供更好的 了解两者共有的结构特征。我们 我还计划制备稳定而有效的2-花生四烯基甘油类似物 这将大大增强我们充分描述其特征的能力 药理特性。这些类比将被评估为CB1和 Cb2受体亲和力，激活35/S-GTP-GammaS结合，在 小鼠四分体实验，以及小鼠和大鼠药物鉴别。我们会 还寻求新的线索，使CB1的衍生品具有选择性 拮抗剂SR141716A。而毫无疑问的是，安非他明与 与大麻素受体产生相似的药理作用 与Delta/9-THC相比，它们在以下几个方面存在差异 药理特征。我们会进行研究，以确定 阿南达胺和Delta9-THC之间的这些差异是由于 药代动力学或药效学因素。将进行研究 为了更清楚地定义大脑中的阿南达胺水平之间的关系 以及它产生的药理作用，并确定是否 代谢抑制剂对其药理作用的操纵 伴随着效力上的变化。目前，它还没有 似乎番荔枝甲胺能够产生耐受性或 依赖程度与Delta/9-THC相同。几种不同的策略 将被用来确定阿南达胺是否能产生健壮的 宽容。对阿南达胺产生耐受性的条件 将被用来评估阿南达胺的依赖倾向。发展 对阿南达胺的依赖表明内源性系统的作用 在成瘾障碍中，而阿南达胺不能产生 依赖性将提供进一步的证据，证明THC和 花青胺是不一样的。稳定有效的类似物的开发 2-花生四烯基甘油的含量将使我们能够评估耐受性和 这种内源性配体的依赖易感性也是如此。再来一次 评价阿南达胺类THC性质的方法是使用 小鼠和大鼠的药物歧视。将尝试进行训练 动物服用高剂量和低剂量的THC，这将增加 发现阿南达胺类THC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.