title: Structure-activity relationships of IKM-159: Diverted synthesis and biological evaluation of a series of C5-oxy analogs.
abstract: Ligands for neuronal receptors are important for understanding the biological functions as well as for treatment of neuronal diseases associated with. Here, we report diverted synthesis and biological evaluation of four C-ring analogs of IKM-159, a subtype-selective inhibitor for (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA)-type ionotropic glutamate receptor. Starting from iodinated 7-oxanorbornene 7, those analogs 3-6 were successfully synthesized in 7.0-33% yields over 8-11 steps via a common intermediate 13. Intracerebroventricular injection of those analogs on mice showed that introduction of oxo group on the C-ring (analogs 4, 5) or cleavage of the C-ring (analog 6) caused significant loss of the activity, while the ether analog 3 still retain the suppressed motor activity, indicating the importance of the C-ring in the neuronal activity of IKM-159.
authors: Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan.
authors: Manami
authors: M
authors: Chiba
authors: Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan.
authors: Chikako
authors: C
authors: Fujimoto
authors: Faculty of Fisheries Sciences, Hokkaido University, Hakodate 041-8611, Japan.
authors: Ryuichi
authors: R
authors: Sakai
authors: Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan. Electronic address: moikawa@yokohama-cu.ac.jp.
authors: Masato
authors: M
authors: Oikawa
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D051379:Mice; D015394:Molecular Structure; D009068:Movement / Q000187:drug effects*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; C552887:IKM 159; D011760:Pyrrolidinones; D058468:Receptors, Ionotropic Glutamate
keywords: Anti-Wacker reaction; Diverted synthesis; Domino metathesis reaction; Glutamate analogs; Ionotropic glutamate receptor