UNIQUE PROBES FOR CANNABINOID RECEPTORS

独特的大麻素受体探针

• 批准号: 6337057
• 负责人: Brian F Thomas
• 金额: $ 1.85万
• 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/6337057
• 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.

源自SR141716A的化合物的合成，SR141716A是Delta9-THC和大麻型的有效拮抗剂，可能导致鉴定出独特的拮抗剂，反向激动剂，以及新的结构性激动剂类别。 这些努力将进一步了解大麻素结构活性关系，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大脑功能有关的生化工具和潜在的药物。 CB2受体的特定拮抗剂的发展也将有助于我们理解激动剂和拮抗剂与大麻素受体亚型的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表明，SR141716A的类似物可以具有独特的特征：对大麻素受体的高亲和力，以及对神经元大麻素的人群的亲和力，与与大种群相区别的神经元大麻素结合位点，该群体与大麻素蛋白素的结合。 这些类似物的结构活性关系与SR141716A的药物叠加与Delta9-THC和其他大麻素的覆盖层是一致的，这些覆盖物和其他大麻素可以确定大麻素激动剂和拮抗剂和拮抗剂之间的相似性和差异的区域，并用作进一步检查这些化合物的结构需求的范式。 由Delta9-THC设计的化合物包括探测侧链结构类比的类似物，探测假定的拮抗剂赋予相互作用的类似物，Pyran氧相互作用的类似物以及吡唑 /苯酚 /苯酚对应类似物。 评估这些类似物的药理测定将包括[3H] SR141716A和[3H] CP-55,940的比较受体结合测定，并在大鼠脑制剂中进行，并转染的细胞系以建立每种化合物的亲和力和选择性。 使用[35S] GTP-GAMMA-S的接受信号转导测定将在选定的化合物上进行表征其功效。 最高兴趣的类似物也将在小鼠和大鼠中的分离组织（小鼠VAS递延和豚鼠回肠）和体内进行测试，以鉴定具有原位和体内活性的化合物。在完成药理学分析后，该研究计划旨在继续以迭代方式测试和进化大麻素结构活性关系的计算模型。