Analysis of relationships between structure and activity of beta _3-adrenoceptor agonists and antagonists by molecular modeling

分子模型分析β_3-肾上腺素受体激动剂和拮抗剂的结构与活性关系

• 批准号: 08670127
• 负责人: NAGATOMO Takafumi
• 金额: $ 1.41万
• 依托单位: Department of Pharmacology, Niigata College of Pharmacy
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670127/
• 关键词: beta-blocker; beta_3-adrenoceptor; molecular modeling; ラット; 白色脂肪組織; β_3-受容体; 結合実験法; ^3H-CGP12177

(Object)The object of this study was to examine (1)evaluation of several agonists antagonists for affinities to beta _3-adrenoceptor (beta _3-AR) in rat white adipose tissues (WAT) and (2)relationships between structure and activity of beta_3-ARs agonists and antagonists by molecular modeling. The method for these experiments were used the radioligand binding assay and the molecular modeling. (Results and Discussion) (1)high affinity binding sites (beta_2-AR) and low affinity binding sites (beta_3-AR) coexisted in WAT.(2) High affinity of selective beta_3-AR agonists (BRL37344A,BRL35135A,SR59230A) to beta_3-AR in WAT were obtained. On the other hand, low affinity of propranolol and bopindolol to this subtype was also obtained. (3) Through modeling, possible binding sites for bopindolol and propranolol involved the 3,4,5 and 6 helices of the beta_3-ARs as hypothesized. Amino, benzoic, and indole methyl functional groups possibly interacted with the Asp117 (helix 3), Ser169 (helix 4), an … More d Ala311 (helix6), respectively. The t-butyl group of bopindolol could interact with the Val116 (helix 3), Pro307 (helix6) and Cys304 (helix 6) residues and the phenyl group could interact with the Val217 and Pro216 (helix5). In addition, the indole ring possibly interacted with the Trp113 (helix 3) and Phe308 (helix 6) residues. In a comparison between the naphthalene group of propranolol and the indole methyl group of bopindolol, less interaction of naphthalene group was qualitatively observed than that of indole methyl group of bopindolol In the beta_3-AR,although the mechanism of binding of both of naphthalene and indole group binding is almost same. While there is interaction of the indole group of bopindolol to Val292 in the beta_2-AR,no interaction by the napthalene group of propranolol to Val292 was observed. Conversely, interactions of the t-butyl group of bopindolol and isopropyl group of propranolol were hypothesized to occur at the same residues in the receptor. In beta_3-AR,different amino acids also affected on the interaction between ligands and beta_3-ARs. Less

（目的）本研究的目的是（1）评价几种激动剂和拮抗剂对大鼠白色脂肪组织（WAT）β_3-肾上腺素受体（β_3-AR）的亲和力;（2）通过分子模拟研究β_3-AR激动剂和拮抗剂的结构与活性的关系。实验方法采用放射配体结合分析和分子模拟。结果与讨论：（1）WAT中存在高亲和力结合位点（β_2-AR）和低亲和力结合位点（β_3-AR）。(2)在WAT中，选择性β_3-AR激动剂（BRL 37344 A、BRL 35135 A、SR 59230 A）对β_3-AR具有高亲和力。另一方面，普萘洛尔和波吲哚洛尔对该亚型的亲和力也较低。(3)通过模型模拟，推测bopindolol和propranolol可能的结合位点位于β_3-AR的3、4、5和6个螺旋上。氨基，苯甲酸和吲哚甲基官能团可能与Asp 117（螺旋3），Ser 169（螺旋4）， ...更多信息 d分别为Ala 311（helix 6）。bopindolol的叔丁基可与Val 116（螺旋3）、Pro 307（螺旋6）和Cys 304（螺旋6）残基相互作用，苯基可与Val 217和Pro 216（螺旋5）残基相互作用。此外，吲哚环可能与Trp 113（螺旋3）和Phe 308（螺旋6）残基相互作用。在β_3-AR中，普萘洛尔的萘基与博吲哚洛尔的吲哚甲基的结合机制基本相同，但萘基的相互作用比博吲哚洛尔的吲哚甲基的小。在β_2-AR中，Bopindolol的吲哚基与Val 292有相互作用，而普萘洛尔的萘基与Val 292无相互作用。相反，假设波吲哚洛尔的叔丁基和普萘洛尔的异丙基的相互作用发生在受体中的相同残基处。在β_3-AR中，不同氨基酸也影响配体与β_3-AR的相互作用。少

项目成果

Kubo, S., et al.: "Assessment of beta_2-and beta _3-Adrenoceptors in Rat white Adipose Tissue by Radioligand Binding Assay." Biol.Pharm.Bull. 20(February). 142-148 (1997)

Kubo, S., 等人：“通过放射性配体结合测定评估大鼠白色脂肪组织中的 β_2-和 β_3-肾上腺素受体。”

Kubo et al.: "Assessment of β_2- and β_3- Adrenoceptors in Rat White Adipose Tssues by Radioligand Binding Assay" Biological & Pharmaceutical Bulletin. 20(2). 142-148 (1997)

Kubo 等人：“通过放射性配体结合测定评估大鼠白色脂肪组织中的 β_2- 和 β_3- 肾上腺素受体”《生物与制药通报》20(2) (1997)。

長友 孝文 他: "Molecular modelingによる非選択的β遮断薬ボピンドロールとβ_2-アドレナリン性受容体サブタイプとの相互作用部位の解析" 心臓. (1998)

Takafumi Nagatomo 等人：“通过分子模型分析非选择性 β 受体阻滞剂波吲洛尔与 β_2 肾上腺素受体亚型之间的相互作用位点”Cardiac (1998)。

Nagatomo, T., et al.: "Analysis of binding sites of non-selective beta-blocker, bopindolol, with beta-adrenoceptor subtypes by molecular modeling. (in Japanese)" HEART. (in press). (1998)

Nagatomo, T. 等人：“通过分子模型分析非选择性 β 受体阻滞剂波吲洛尔与 β 肾上腺素受体亚型的结合位点。（日语）”HEART。

Kubo et al: "Assessment of β_2- and β_3-Adrenocceptors in Rat White Adipose Tissues by Radioligand Binding Assay" Biol.Pham.Bull.20. 142-148 (1997)

Kubo 等人：“通过放射性配体结合测定评估大鼠白色脂肪组织中的 β_2- 和 β_3-肾上腺素受体”Biol.Pham.Bull.20 (1997)。