UNIQUE PROBES FOR CANNABINOID RECEPTORS

独特的大麻素受体探针

• 批准号: 2747791
• 负责人: Brian F Thomas
• 金额: $ 18万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2747791
• 关键词: X ray crystallography; analog; animal tissue; behavior test; biological signal transduction; cannabinoid receptor; cannabinoids; chemical structure function; computer simulation; conformation; drug design /synthesis /production; guanosine triphosphate; inhibitor /antagonist; laboratory mouse; laboratory rat; molecular dynamics; psychopharmacology; receptor binding; receptor sensitivity

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.

SR141716A是一种有效的δ 9- thc拮抗剂和大麻模拟物，其衍生化合物的合成可能导致鉴定独特的拮抗剂、逆激动剂以及一种新的结构类型的激动剂。这些努力将进一步加深我们对大麻素结构-活性关系的理解，促进我们对大麻素神经化学系统的理解，并提供与药物滥用和脑功能相关的生化工具和潜在药物。CB2受体特异性拮抗剂的开发也将有助于我们了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结果，表明SR141716A的类似物可以合成具有独特特征的物质：对大麻素受体具有高亲和力，并且对大麻素结合位点的神经元群体具有亲和力，这与大麻素激动剂结合的群体不同。这些类似物的结构-活性关系与SR141716A与δ 9- thc和其他大麻素的药效覆盖一致，这识别了大麻素激动剂和拮抗剂之间的相似和差异区域，并为进一步研究这类化合物的结构要求提供了一个范式。基于δ 9-四氢大麻酚分子覆盖层设计的化合物包括探测侧链结构的类似物、探测假定的拮抗剂赋予相互作用的类似物、吡喃氧相互作用的类似物和吡唑/苯酚对应的类似物。评估这些类似物的药理学分析将包括在大鼠脑制剂和转染细胞系中与[3H]SR141716A和[3H]CP-55,940进行比较受体结合试验，以确定每种化合物的亲和力和选择性。将使用[35S] gtp - γ - s对选定的化合物进行公认的信号转导试验，以表征其功效。最感兴趣的类似物也将在分离组织（小鼠输精管和豚鼠回肠）和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，研究计划旨在继续测试并以迭代的方式发展大麻素结构-活性关系的计算模型。