Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists
| Autor: | Seiji Ogawa, Toru Maruyama, Takuya Okada, Kousuke Tani, Yoshikazu Goto, Shinsaku Yamane, Toshihide Watanabe, Akio Watanabe, Kazuma Tsuboi, Kazumi Moriyuki, Hiroyuki Takeda, Atsushi Kinoshita |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class G protein Stereochemistry Clinical Biochemistry Pharmaceutical Science Biochemistry 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine GTP-binding protein regulators GTP-Binding Proteins Drug Discovery medicine Functional selectivity Moiety Structure–activity relationship Humans Cyclopentane Molecular Biology Chemistry Organic Chemistry Receptors Prostaglandin E EP2 Subtype 030104 developmental biology Molecular Medicine Drug Screening Assays Antitumor Selectivity Oligopeptides 030217 neurology & neurosurgery |
| Zdroj: | Bioorganicmedicinal chemistry letters. 26(10) |
| ISSN: | 1464-3405 |
| Popis: | The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in β-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity. |
| Databáze: | OpenAIRE |
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