CANNABINOID RECEPTOR LIGANDS--SAR

Delta9-四氢大麻酚(THC)是大麻素的主要中枢活性成分 大麻或大麻(大麻)。幂等三环和双环 辉瑞中心研究中心开发的大麻素类似物被用于 阐明Delta9-THC的细胞作用机制。我们决定 模拟大麻的化合物与大麻素受体相互作用 调节循环AMP第二信使系统的神经细胞。我们 利用强效双环大麻素建立了放射性配基结合分析方法 激动剂[~3H]CP-55940，并将其用于生化和 对大麻素受体进行药理学研究。 这个项目的目标是研究大麻素受体-配体。 在细胞和分子水平上的相互作用。这项工作将继续下去 通过以下具体目标： 1.继续表征新型亲和配体和正电子发射 断层扫描(PET)配体； 2.鉴定中枢神经系统中存在的大麻素样结合活性，以及 鉴定和提纯导致这一活动的因素(S)；以及 3.建立大麻样结合因子的免疫分析方法(S)。 预计内源性的测定和表征 大麻素样结合因子(S)对大麻素受体的作用 新的构效关系研究进展 这种新的分子。这一知识可能会导致 可能对大麻素受体有用的拮抗剂。此外, 内源性大麻素样结合因子的受体亚型可能 被追寻。这些研究将促进我们对 大麻感受性神经元在镇痛、认知记忆和运动中的作用 行为。

Delta9-Tetrahydrocannabinol (THC) is the primary CNS-active component of marijuana or hashish (Cannabis sativa). Potent tricyclic and bicyclic cannabinoid analogs developed at Pfizer Central Research were utilized to elucidate a cellular mechanism of action for delta9-THC. We determined that cannabimimetic compounds interact with a cannabinoid receptor on neuronal cells which regulates the cyclic AMP second messenger system. We developed a radioligand binding assay using the potent bicyclic cannabinoid agonist [3H]CP-55940, and have used it to biochemically and pharmacologically characterize the cannabinoid receptor. The goal of this project is to study cannabinoid receptor-ligand interactions at the cellular and molecular levels. This work will continue through the following specific aims to: 1.Continue characterization of novel affinity ligands and positron emission tomography (PET) scanning ligands; 2.Identify a cannabinoid-like binding activity present in the CNS, and characterize and purify the factor(s) responsible for this activity; and 3.Develop an immunoassay for the cannabinoid-like binding factor(s). It is expected that the determination and characterization of an endogenous cannabinoid-like binding factor(s) for the cannabinoid receptor will allow the development of new structure-activity relationship studies based on this novel molecule. This knowledge could lead to the development of potentially useful antagonists for the cannabinoid receptor. In addition, receptor subtypes for the endogenous cannabinoid-like binding factor could be sought. These studies will advance our understanding of the role of cannabinoceptive neurons in analgesia, cognition and memory, and motor behaviors.