Design, synthesis, and biological evaluation of tricyclic heterocycle-tetraamine conjugates as potent NMDA channel blockers.
We have developed a new class of N-methyl-d-aspartate (NMDA) channel blockers having a conjugate structure that consists of a nitrogenous heterocyclic head and a tetraamine tail. Among them, dihydrodibenzazepine-homospermine conjugate (8) exhibited potent antagonistic activity at NR1/NR2A or NR1/NR2B NMDA subtype receptors compared with the lead compound, AQ343 (1), or memantine, as well as weak cytotoxicity. Its superior biological profiles compared with known compounds point to its potential use as therapeutic agents for neurological disorders.
Takayama
Hiromitsu
H
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. takayama@p.chiba-u.ac.jp
Yaegashi
Yuichi
Y
Kitajima
Mariko
M
Han
Xia
X
Nishimura
Kazuhiro
K
Okuyama
Shigeru
S
Igarashi
Kazuei
K
D000588:Amines / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000588:Amines; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate