UNIQUE PROBES FOR CANNABINOID RECEPTORS

SR 141716 A是delta 9-THC和大麻拟似物的有效拮抗剂，其衍生化合物的合成可能导致鉴定独特的拮抗剂、反向激动剂以及新结构类别的激动剂。 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剂。CB 2受体的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的选择性相互作用的结构要求。 拟议研究的具体目标是基于初步研究的结果，表明SR 141716 A的类似物可以合成具有独特特征：对大麻素受体的高亲和力，以及对神经元大麻素结合位点群体的亲和力，该群体与大麻素激动剂结合的群体可区分。 这些类似物的结构-活性关系与SR 141716 A与δ 9-THC和其他大麻素的药效学重叠一致，其鉴定了大麻素激动剂和拮抗剂之间的相似性和差异性区域，并用作进一步检查这些类别化合物的结构要求的范例。 从这种分子与δ 9-THC的重叠设计的化合物包括探测侧链结构类似物的那些、探测赋予相互作用的推定拮抗剂的类似物、吡喃氧相互作用的类似物和吡唑/苯酚对应类似物。 评价这些类似物的药理学试验将包括在大鼠脑制备物和转染细胞系中使用[3 H] SR 141716 A和[3 H]CP-55，940进行的比较受体结合试验，以确定每种化合物的亲和力和选择性。 将对选定的化合物进行使用[35 S]GTP-gamma-S的公认信号转导试验，以表征其功效。 最感兴趣的类似物也将在分离的组织（小鼠输精管和豚鼠回肠）中以及在小鼠和大鼠体内进行测试，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，该研究计划旨在以迭代方式继续测试和发展大麻素结构-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.