UNIQUE PROBES FOR CANNABINOID RECEPTORS

SR141716A是Delta9-THC和大麻仿制药的有效拮抗剂，其化合物的合成可能导致独特的拮抗剂、反向激动剂以及一类新的结构类型的激动剂的鉴定。这些努力将加深我们对大麻素构效关系的了解，促进我们对大麻素神经化学系统的了解，并提供与药物滥用和大脑功能相关的生化工具和潜在的药物制剂。CB2受体特异性拮抗剂的开发也将有助于我们理解激动剂和拮抗剂与大麻素受体亚型选择性相互作用的结构要求。拟议研究的具体目的是基于初步研究的结果，该结果表明可以合成具有独特特征的SR141716A类似物：对大麻素受体的高亲和力，以及与大麻素激动剂结合的人群相区别的神经元大麻素结合位点的亲和力。这些类似物的构效关系与SR141716A与Delta9-THC和其他大麻素的药理重叠是一致的，它确定了大麻素激动剂和拮抗剂之间的相似和不同区域，并作为进一步研究这些类化合物的结构要求的范例。从Delta9-THC分子覆盖层设计的化合物包括探测侧链结构类似物、探测可能的拮抗剂相互作用的类似物、吡喃氧相互作用的类似物和吡唑/苯酚对应类似物。评估这些类似物的药理学分析将包括与[~H]SR141716A和[~H]CP-55,940在大鼠脑标本和转基因细胞系中的比较受体结合分析，以确定每种化合物的亲和力和选择性。将对选定的化合物进行使用[35S]GTP-伽马-S进行的公认的信号转导试验，以表征它们的有效性。最感兴趣的类似物也将在分离的组织(小鼠输精管和豚鼠回肠)以及在小鼠和大鼠体内进行测试，以确定具有原位和体内活性的化合物。在完成药理学分析后，该研究计划打算继续以迭代的方式测试和发展大麻类化合物结构-活性关系的计算模型。

The synthesis of compounds derived from SR141716A, a potent antagonist of delta9-THC and cannabimimetics, may lead to the identification of unique antagonists, inverse agonists, as well as a new structural class of agonists. These efforts would further our understanding of cannabinoid structure-activity relationships, facilitate our understanding of the cannabinoid neurochemical system and provide biochemical tools and potential medicinal agents relevant to drug abuse and to brain function. The development of specific antagonists for the CB2 receptor would also contribute to our understanding of the structural requirements for selective interactions of both agonists and antagonists with cannabinoid receptor subtypes. The specific aims of the proposed research are based on results of preliminary studies showing that analogs of SR141716A could be synthesized with unique characteristics: high affinity for cannabinoid receptors, and affinity for a population of neuronal cannabinoid binding sites that is distinguishable from the population to which cannabinoid agonists bind. These analogs' structure-activity relationships are consistent with a pharmacophoric overlay of SR141716A with delta9-THC and other cannabinoids which identifies regions of similarity and of disparity between Cannabinoid agonists and antagonists and serves as a paradigm for further examining the structural requirements of these classes of compounds. Compounds designed from this molecular overlay with delta9-THC include those probing the side chain structural analogy, analogs probing the putative antagonist conferring interaction, analogs of the pyran oxygen interaction and pyrazole / phenol correspondence analogs. Pharmacological assays to evaluate these analogs will include a comparative receptor binding assay with [3H]SR141716A and [3H]CP-55,940 in rat brain preparations and transfected cell lines to establish each compounds affinity and selectivity. An accepted signal transduction assay using [35S]GTP-gamma-S will be performed on selected compounds to characterize their efficacy. Analogs of highest interest will also be tested in isolated tissues (mouse vas deferens and guinea pig ileum) and in vivo in the mouse and rat to identify compounds with in situ and in vivo activity. Upon completion of pharmacological profiling, the research program is intended to continue to test and evolve a computational model of cannabinoid structure-activity relationships in an iterative fashion.