title: In vitro and in vivo evaluation of polymethylene tetraamine derivatives as NMDA receptor channel blockers.
abstract: The biological activities of six symmetrically substituted 2-methoxy-benzyl polymethylene tetraamines (1-4) and diphenylethyl polymethylene tetraamines (5 and 6) as N-methyl-D-aspartate (NMDA) receptor channel blockers, were evaluated in vitro and in vivo. Although all compounds exhibited stronger channel block activities in comparison to memantine in Xenopus oocytes voltage clamped at -70 mV, only compound 2 (0.4 mg/kg intravenous injection) decreased the size of brain infarction in a photochemically induced thrombosis model mice at the same extent of memantine (10mg/kg intravenous injection). Other compounds (1, 3, 4, 5 and 6) did not decrease the size of brain infarction significantly due to the limited injection doses. The present study suggests that compound 2 could represent a valuable lead compound to design low toxicity polyamines for clinical use against stroke.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Saiki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yoshizawa
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchetti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Toida
authors.forename: Keiko
authors.initials: K
authors.lastname: Kashiwagi
authors.forename: Kazuei
authors.initials: K
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008559:Memantine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D011073:Polyamines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C474278:polymethylene tetraamine; D008559:Memantine