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

（目的）本研究的目的是研究(1)评价几种激动剂和拮抗剂对大鼠白色脂肪组织(WAT) β _3-肾上腺素能受体（β _3-AR）的亲和力；(2)通过分子模型研究β _3-AR激动剂和拮抗剂的结构和活性之间的关系。实验方法采用放射配体结合实验和分子模拟。（结果与讨论）(1)高亲和力结合位点（beta_2-AR）和低亲和力结合位点（beta_3-AR）在WAT中共存。(2)获得了选择性β - 3- ar激动剂（BRL37344A、BRL35135A、SR59230A）对WAT β - 3- ar的高亲和力。另一方面，心得洛尔和博品多洛尔对该亚型的亲和力也较低。(3)通过建模，bopindolol和心得安可能的结合位点与假设的β 3- ars的3、4、5和6螺旋有关。氨基、苯甲酸和吲哚甲基官能团可能分别与Asp117（螺旋3）、Ser169（螺旋4）和Ala311（螺旋6）相互作用。bopindolol的t-丁基可与Val116（螺旋3）、Pro307（螺旋6）和Cys304（螺旋6）残基相互作用，苯基可与Val217和Pro216（螺旋5）相互作用。此外，吲哚环可能与Trp113（螺旋3）和Phe308（螺旋6）残基相互作用。对比心得洛尔的萘基团和吲哚多洛尔的吲哚甲基，定性观察到萘基团比吲哚多洛尔的吲哚甲基在β - 3- ar中的相互作用少，尽管萘和吲哚基团的结合机制几乎相同。在β 2- ar中，bopindolol的吲哚基团与Val292存在相互作用，而心得安的萘基团与Val292没有相互作用。相反，bopindolol的t-丁基和心得安的异丙基的相互作用被假设发生在受体的相同残基上。在β - 3- ar中，不同的氨基酸对配体与β - 3- ar的相互作用也有影响。少

(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