title: Discovery of diaminobutane derivatives as Ca(2+)-permeable AMPA receptor antagonists.
abstract: We designed and synthesized a series of the polyamine derivatives as potent Ca(2+)-permeable AMPA receptor antagonists. In the course of this study, we found that the polyamine derivatives exhibited strong hypotensive activity which was undesirable activity for neuroprotective agents. Therefore, we tried to find non-hypotensive antagonists by structural modification of such compounds. Through this derivatization, we obtained the diamine compounds having desired profiles. Especially, compound 8f, which was non-hypotensive and potent Ca(2+)-permeable AMPA receptor antagonist, showed neuroprotective effects in transient global ischemia models in gerbils.
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 16-13, Kitakasai 1-Chome, Edogawa-ku, 134-8630, Tokyo, Japan. yoned10z@daiichipharm.co.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Tetuya
authors.initials: T
authors.lastname: Mimura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawagoe
authors.forename: Takanori
authors.initials: T
authors.lastname: Yasukouchi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tatematu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ito
authors.forename: Masaki
authors.initials: M
authors.lastname: Saito
authors.forename: Masunobu
authors.initials: M
authors.lastname: Sugimura
authors.forename: Fusako
authors.initials: F
authors.lastname: Kito
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawajiri
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003959:Diamines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D004195:Disease Models, Animal; D005849:Gerbillinae; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D003959:Diamines; D018091:Receptors, AMPA; D002118:Calcium