Analogs: Unique Probes for Cannabinoid Receptors

类似物：大麻素受体的独特探针

• 批准号: 7071769
• 负责人: Brian F Thomas
• 金额: $ 35.8万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071769
• 关键词: amides; analog; animal tissue; cannabinoid receptor; chemical synthesis; computational neuroscience; inhibitor /antagonist; neuropharmacology; receptor binding; receptor expression; tissue /cell preparation; transfection

DESCRIPTION (provided by applicant): 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 can also 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 dysfunction. The specific aims of the proposed research are based on results of studies conducted in our laboratory showing that analogs of SR141716A could be synthesized with unique characteristics: high affinity for cannabinoid receptors, and that are able to fully displace [3H]CP55940 and [3H]SR141716A with reasonable affinity, while simultaneously much less able, or unable, to displace [3H]WIN55212-2. In addition, we have evidence to suggest that because of this binding selectivity, these compounds possess a unique profile of pharmacological activity. These results suggest that it might be necessary to change current paradigms of cannabinoid ligand-receptor interaction, and this could lead to innovative approaches to investigating, and manipulating the pharmacology of cannabinoids. The diverse structures of compounds generated to date appear amenable to three dimensional structure-activity relationship analyses, which serves as a paradigm for the further design, synthesis and testing of the structural requirements of this class of compounds in an iterative fashion. Compounds intended for synthesis comprise a systematic structural modification of each substituent position of the pyrazole nucleus and also include alternative pyrazole, imidazoles and pyrazolo [l,5-f] phenanthridine ring systems where the substituents may or may not maintain the original spacial relationships in SR141716A. Bivalent ligands derived from SR141716A are also proposed, and we believe this represents the first synthesis of bivalent ligands to probe for CB1 oligomerization. Pharmacological assays to evaluate these analogs will continue to include a comparative receptor binding assay with [3H]SR141716A, [3H]CP55940 and [3H]WIN55212-2 in human and rat brain preparations and transfected cell lines expressing CB1 or CB2 receptors to establish each compounds affinity and selectivity. An accepted signal transduction assay using GTP-gamma-[35S] will be performed on selected compounds to characterize their efficacy and ability to antagonize other cannabimimetic ligands, particularly CP55940 and WIN55212-2. 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.

描述（由申请人提供）：源自SR141716A的化合物的合成，SR141716A是Delta9-THC和大麻imimimetics的有效拮抗剂，可能导致鉴定独特的拮抗剂，反激动剂，以及一种新的结构性痛苦类别。这些努力还可以进一步了解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障碍有关的生化工具和潜在的药物。拟议的研究的具体目的是基于我们实验室中进行的研究结果表明，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，并且能够完全取代[3H] CP55940和[3H] SR141716A，而同样的相似性，或者在合理的相似之处，或者同样相似地置于合理的范围。 [3H] WIN55212-2。此外，我们有证据表明，由于具有这种结合的选择性，这些化合物具有独特的药理学活性特征。这些结果表明，可能有必要改变大麻素配体 - 受体相互作用的当前范式，这可能导致研究和操纵大麻素的药理学的创新方法。迄今为止生成的化合物的各种结构似乎适合三维结构 - 活性关系分析，这是以迭代方式进一步设计，合成和测试此类化合物的结构要求的范式。旨在合成的化合物包括吡唑核每个定位位置的系统结构修饰，还包括替代性吡唑，咪唑和吡唑洛唑[l，5-F]苯拥tanththridine环系统，在SR1414141414116A中可能会或可能无法维持原始的空间关系。还提出了源自SR141716A的二价配体，我们认为这代表了二价配体探测C​​B1寡聚化的首次合成。评估这些类似物的药理测定将继续包括[3H] SR141716A，[3H] CP55940和[3H] WIN55212-2的比较受体结合测定法，并在人类和大鼠脑制剂中进行win55212-2，以及表达CB1或CB2受体的转染细胞系，表达CB1或CB2受体，以建立每个化合物和选择性。使用GTP-gamma- [35S]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和能力与其他大麻含量配体拮抗，尤其是CP55940和WIN555212-2。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。

项目成果

Conformationally constrained analogues of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716): design, synthesis, computational analysis, and biological evaluations.

• DOI: 10.1021/jm8000778
• 发表时间: 2008-05
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Yanan Zhang;Jason P. Burgess;M. Brackeen;A. Gilliam;S. Mascarella;Kevin M Page;H. Seltzman;B. F. Thomas

Conformational characteristics of the interaction of SR141716A with the CB1 cannabinoid receptor as determined through the use of conformationally constrained analogs.

通过使用构象受限类似物确定 SR141716A 与 CB1 大麻素受体相互作用的构象特征。

• DOI: 10.1208/aapsj080476
• 发表时间: 2006
• 期刊: The AAPS journal
• 作者: Thomas,BrianF;Zhang,Yanan;Brackeen,Marcus;Page,KevinM;Mascarella,SWayne;Seltzman,HerbertH
• 通讯作者: Seltzman,HerbertH

Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor.

• DOI: 10.1021/jm1006676
• 发表时间: 2010-10-14
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhang Y;Gilliam A;Maitra R;Damaj MI;Tajuba JM;Seltzman HH;Thomas BF
• 通讯作者: Thomas BF