Discovery of diaminobutane derivatives as Ca(2+)-permeable AMPA receptor antagonists.
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.
Yoneda
Yoshiyuki
Y
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 16-13, Kitakasai 1-Chome, Edogawa-ku, 134-8630, Tokyo, Japan. yoned10z@daiichipharm.co.jp
Mimura
Tetuya
T
Kawagoe
Keiichi
K
Yasukouchi
Takanori
T
Tatematu
Toshiaki
T
Ito
Masayuki
M
Saito
Masaki
M
Sugimura
Masunobu
M
Kito
Fusako
F
Kawajiri
Shinichi
S
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
D003959:Diamines; D018091:Receptors, AMPA; D002118:Calcium