title: Behavioral studies on FR115427, a novel selective N-methyl-D-aspartate antagonist.
abstract: Behavioral and in vitro receptor binding methods were used to evaluate and compare the effects of FR115427 ((+)-l-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride) with those of MK801, a non-competitive NMDA antagonist. FR115427 inhibited NMDA-induced convulsions in mice by intracerebroventrical(ICV) and systematic injection. FR115427 was found to be about ten times less potent than MK801. Furthermore, the inhibitory effect of FR115427 and MK801 on NMDA-induced convulsions was evaluated in time course studies in mice. MK801 exhibited a more sustained anticonvulsive activity than FR115427. In addition, PCP-like behaviors were examined in mice after ICV injection of these compounds. At the lowest dose FR115427 significantly increased locomotor activity, although the effect of this compound was about hundred times less potent than that of MK801. At higher dose a more complex pattern of behavior, e.g. head-movement and eventually ataxia was observed. In binding assays with rat brain membranes, FR115427 inhibited the binding of (3H)TCP (IC50 = 0.249 microM) and (3H)MK801 (IC50 = 0.312 microM) but did not inhibit the binding of (3H)CPP or (3H)glycine. These results suggest that FR115427 is a novel non-competitive NMDA antagonist that acts on a binding site located within the NMDA receptor associated ion channel.
authors.affiliation: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nakanishi
authors.forename: K
authors.initials: K
authors.lastname: Katsuta
authors.forename: Y
authors.initials: Y
authors.lastname: Ueda
authors.forename: H
authors.initials: H
authors.lastname: Takasugi
authors.forename: A
authors.initials: A
authors.lastname: Kuno
authors.forename: M
authors.initials: M
authors.lastname: Ohkubo
authors.forename: K
authors.initials: K
authors.lastname: Ogita
authors.forename: Y
authors.initials: Y
authors.lastname: Yoneda
authors.forename: K
authors.initials: K
authors.lastname: Shirakawa
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044005:Tetrahydroisoquinolines
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D044005:Tetrahydroisoquinolines; C084456:1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline; D016291:Dizocilpine Maleate; C012058:tenocyclidine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D010622:Phencyclidine