title: Structure-activity relationship study at C9 position of kaitocephalin.
abstract: Kaitocephalin (KCP) isolated from Eupenicillium shearii PF1191 is an unusual amino acid natural product in which serine, proline, and alanine moieties are liked with carbon-carbon bonds. KCP exhibits potent and selective binding affinity for one of the ionotropic glutamate receptor subtypes, NMDA receptors (Ki=7.8nM). In this study, new structure-activity relationship studies at C9 of KCP were implemented. Eleven new KCP analogs with different substituents at C9 were prepared and employed for binding affinity tests using native ionotropic glutamate receptors. Replacement of the 3,5-dichloro-4-hydroxybenzoyl group of KCP with a 3-phenylpropionyl group resulted in significant loss of binding affinity for NMDARs (Ki=1300nM), indicating an indispensable role of the aromatic ring of KCP in the potent and selective binding to NMDARs. Other analogs showed potent binding affinity in a range of 11-270nM. These findings would directly link to develop useful chemical tools toward imaging and labeling of NMDARs.
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yasuno
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hamada
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Bioorganic Research Institute, Suntory Foundation for Life Sciences, 8-1-1, Seikadai, Seika-cho, Soraku-gun, Kyoto 619-0284, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimamoto
authors.affiliation: National Institute of Advanced Industrial Science and Technology, 1-8-31, Midorigaoka, Ikeda, Osaka 563-8577, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shigeri
authors.affiliation: Analytical Chemistry, Pharmaceutical Science, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Akizawa
authors.affiliation: Analytical Chemistry, Pharmaceutical Science, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Motomi
authors.initials: M
authors.lastname: Konishi
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Ohfune
authors.affiliation: Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan. Electronic address: shinada@sci.osaka-cu.ac.jp.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shinada
mesh_terms: D004305:Dose-Response Relationship, Drug; D055324:Eupenicillium / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D011758:Pyrroles; D016194:Receptors, N-Methyl-D-Aspartate; C442421:kaitocephalin
keywords: Ionotropic glutamate receptors; Kaitocephalin; NMDA receptors; Natural product; Structure–activity relationship study