title: In vitro and antinociceptive profile of HON0001, an orally active NMDA receptor NR2B subunit antagonist.
abstract: The analgesic activity and side effect liabilities of a novel NR2B antagonist, 7-hydroxy-6-methoxy-2-methyl-1-(2-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (HON0001) were investigated. HON0001 inhibited [3H]MK-801 binding to rat brain membranes in a biphasic manner, with IC50 values of 54.68+/-4.96 nM and 46.48+/-5.85 muM for high- and low-affinity sites, respectively. HON0001 inhibited [3H]ifenprodil binding to membranes of rat cerebral cortex with an IC50 value of 57.01+/-3.4 nM, consistent with the results obtained for high-affinity sites of [3H]MK-801 binding. HON0001 exhibited no or negligible affinity for other receptors, transporters and ion channels, while HON0001 had a moderate agonistic activity at mu-opioid receptors and affinity for dopamine D1 receptors. HON0001 exhibited an analgesic effect in carrageenan-induced mechanical hyperalgesia and in the Seltzer model of partial sciatic nerve ligation following oral administration. In contrast, unlike MK-801, HON0001 did not affect spontaneous locomotor activity, rotarod performance and step-through latency in a passive avoidance task even at doses much higher than antinociceptive doses. HON0001 exhibited excellent brain penetration with a brain-to-plasma ratio of 34.5. These findings show that HON0001 is an orally active NR2B antagonist and that it may be useful for treating patients with neuropathic and other conditions without causing the side effects often observed with currently available non-subtype selective NMDA receptor antagonists.
authors.affiliation: Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Saitama 331-9530, Japan.
authors.forename: Sayoko
authors.initials: S
authors.lastname: Suetake-Koga
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shimazaki
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takamori
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kanuma
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sekiguchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Toyohiko
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Matsui
authors.forename: Toshio
authors.initials: T
authors.lastname: Honda
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: C513822:7-hydroxy-6-methoxy-2-methyl-1-(2-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; D000700:Analgesics; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate