title: Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.
abstract: 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.
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan. Electronic address: s.ogawa@ono.co.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Biology & Pharmacology, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Moriyuki
authors.affiliation: Department of Biology & Pharmacology, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Discovery Research Alliance, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Yamane
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Tsuboi
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Okada
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Discovery Research Alliance, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tani
authors.affiliation: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D004354:Drug Screening Assays, Antitumor / Q000379:methods; D019204:GTP-Binding Proteins / Q000737:chemistry; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; C545644:PTGER2 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D019204:GTP-Binding Proteins; C555534:Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH
keywords: Agonist; Biased ligand; EP2; Prostaglandin; Structure–functional selectivity relationship