1997 Fiscal Year Final Research Report Summary
Analysis of relationships between structure and activity of beta _3-adrenoceptor agonists and antagonists by molecular modeling
| Project/Area Number |
08670127
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Department of Pharmacology, Niigata College of Pharmacy |
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Principal Investigator |
NAGATOMO Takafumi Niigata College of Pharmacy, Pharmacology, Professor, 薬理学, 教授 (60121240)
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| Co-Investigator(Kenkyū-buntansha) |
TAKATSU Noriyuki Niigata College of Pharmacy, Pharmaceutical Chemistry, Instructor, 薬化学, 講師 (60201597)
KATAYAMA Hajime Niigata College of Pharmacy, Pharmaceutical Chemistry, Professor, 薬化学, 教授 (70113024)
OHNUKI Toshio Niigata College of Pharmacy, Pharmacology, Assistant Professor, 薬理学, 助手 (60288230)
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| Project Period (FY) |
1996 – 1997
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| Keywords | beta-blocker / beta_3-adrenoceptor / molecular modeling |
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| Research Abstract |
(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
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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
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