Pharmacological characterization of novel opioid drugs

新型阿片类药物的药理学特征

• 批准号: 8148552
• 负责人: Richard Rothman
• 金额: $ 77.97万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148552
• 关键词: Opioid; Pharmaceutical Preparations; novel

Significant progress was made in the last reporting period, resulting in five publications. One paper will be highlighted here (Identification of a novel almost neutral micro-opioid receptor antagonist in CHO cells expressing the cloned human mu-opioid receptor. Synapse 64:280-8): "The basal (constitutive) activity of G protein-coupled receptors allows for the measurement of inverse agonist activity. Some competitive antagonists turn into inverse agonists under conditions where receptors are constitutively active. In contrast, neutral antagonists have no inverse agonist activity, and they block both agonist and inverse agonist activity. The mu-opioid receptor (MOR) demonstrates detectable constitutive activity only after a state of dependence is produced by chronic treatment with a MOR agonist. We therefore sought to identify novel MOR inverse agonists and novel neutral MOR antagonists in both untreated and agonist-treated MOR cells. CHO cells expressing the cloned human mu receptor (hMOR-CHO cells) were incubated for 20 h with medium (control) or 10 microM (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-2,1-cpyran-7-carboxylic acid methyl ester (herkinorin, HERK). HERK treatment generates a high degree of basal signaling and enhances the ability to detect inverse agonists. (35)S-GTP-gamma-S assays were conducted using established methods. We screened 21 MOR "antagonists" using membranes prepared from HERK-treated hMOR-CHO cells. All antagonists, including CTAP and 6beta-naltrexol, were inverse agonists. However, LTC-274 ((-)-3-cyclopropylmethyl-2,3,4,4alpha,5,6,7,7alpha-octahydro-1H-benzofuro3,2-eisoquinolin-9-ol)) showed the lowest efficacy as an inverse agonist, and, at concentrations less than 5 nM, had minimal effects on basal (35)S-GTP-gamma-S binding. Other efforts in this study identified KC-2-009 ((+)-3-((1R,5S)-2-((Z)-3-phenylallyl)-2-azabicyclo3.3.1nonan-5-yl)phenol hydrochloride) as an inverse agonist at untreated MOR cells. In HERK-treated cells, KC-2-009 had the highest efficacy as an inverse agonist. In summary, we identified a novel and selective MOR inverse agonist (KC-2-009) and a novel MOR antagonist (LTC-274) that shows the least inverse agonist activity among 21 MOR antagonists. LTC-274 is a promising lead compound for developing a true MOR neutral antagonist."

在最后一个报告期间取得了重大进展，导致五个出版物。一篇论文将在此处突出显示（在表达克隆的人类阿片受体的CHO细胞中鉴定了一种新型中性微型阿片受体拮抗剂。Synapse64：280-8）： “ G蛋白耦合受体的基础（本构）活性可以测量逆激动剂活性。在受体具有构成活性的条件下，某些竞争性拮抗剂会变成反向激动剂。相比之下，中性拮抗剂没有相反的激动剂活性，并且它们仅阻止受体和反向激动剂。依赖性是通过MOR激动剂的慢性处理。 (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-2,1-cpyran-7-carboxylic acid methyl ester (herkinorin, HERK). HERK treatment generates a high degree of basal signaling and enhances检测反向激动剂的能力。 （35）使用已建立的方法进行了S-GTP-GAMMA-S分析。我们使用了从HERK处理的HMOR-CHO细胞制备的膜筛选了21个MOR“拮抗剂”。所有拮抗剂，包括CTAP和6Beta nnletrexol，都是反向激动剂。但是，LTC-274（（（ - ） - 3-周期丙基甲基-2,3,4,4,4Alpha，5,6,7,7,7,7 alpha-octahydro-1H-Benzofuro3，2-2- eisoquinolin-9-Ol）表现出最低的浓度，并且在浓度下效果最低，并且在浓度下效果最低。 （35）S-GTP-GAMMA-S结合。这项研究的其他努力确定了KC-2-009（（（+） - 3 - （（（1r，5s）-2 - （（（Z）-3-苯基甲基甲基）-2-azabicyclo3.3.3.1nonan-5-ill）苯酚盐酸苯酚）是未经培养的MOR细胞中的抗激动剂。在经HERK处理的细胞中，KC-2-009作为反向激动剂的功效最高。总而言之，我们确定了一种新颖而选择性的MOR反向激动剂（KC-2-009）和一种新型MOR拮抗剂（LTC-274），该拮抗剂显示了21种MOR拮抗剂中反向激动剂活性最小。 LTC-274是发展真正的MOR中性拮抗剂的有前途的铅化合物。”