title: Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL.
abstract: We have synthesized a new benzomorphan derivative, 2R-[2alpha,3(S*), 6alpha]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-3-[2-(phenylmethoxy)propyl]-2, 6-methano-3-benzazocin-10-ol hydrochloride (BIII 890 CL), which displaced [(3)H]batrachotoxinin A-20alpha-benzoate from neurotoxin receptor site 2 of the Na(+) channel in rat brain synaptosomes (IC(50) = 49 nM), but exhibited only low affinity for 65 other receptors and ion channels. BIII 890 CL inhibited Na(+) channels in cells transfected with type IIA Na(+) channel alpha subunits and shifted steady-state inactivation curves to more negative potentials. The IC(50) value for the inactivated Na(+) channel was much lower (77 nM) than for Na(+) channels in the resting state (18 microM). Point mutations F1764A and Y1771A in transmembrane segment S6 in domain IV of the alpha subunit reduced the voltage- and frequency-dependent block, findings which suggest that BIII 890 CL binds to the local anesthetic receptor site in the pore. BIII 890 CL inhibited veratridine-induced glutamate release in brain slices, as well as glutamate release and neurotoxicity in cultured cortical neurons. BIII 890 CL (3-30 mg/kg s.c.) reduced lesion size in mice and rats when administered 5 min after permanent focal cerebral ischemia at doses that did not impair motor coordination. In contrast to many other agents, BIII 890 CL was neuroprotective in both cortical and subcortical regions of the rat brain. Our results demonstrate that BIII 890 CL is a potent, selective, and highly use-dependent Na(+) channel blocker that protects brain tissue from the deleterious effects of focal cerebral ischemia in rodents.
authors.affiliation: Departments of Central Nervous System Research, Boehringer Ingelheim Pharma KG, 55216 Ingelheim am Rhein, Germany. carter@ing.boehringer-ingleheim.com
authors.forename: A J
authors.initials: AJ
authors.lastname: Carter
authors.forename: M
authors.initials: M
authors.lastname: Grauert
authors.forename: U
authors.initials: U
authors.lastname: Pschorn
authors.forename: W D
authors.initials: WD
authors.lastname: Bechtel
authors.forename: C
authors.initials: C
authors.lastname: Bartmann-Lindholm
authors.forename: Y
authors.initials: Y
authors.lastname: Qu
authors.forename: T
authors.initials: T
authors.lastname: Scheuer
authors.forename: W A
authors.initials: WA
authors.lastname: Catterall
authors.forename: T
authors.initials: T
authors.lastname: Weiser
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001575:Benzomorphans / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000737:chemistry / Q000502:physiology; D013574:Synaptosomes / Q000502:physiology*; D014162:Transfection; D014701:Veratridine / Q000494:pharmacology
chemical_list: C408069:BIII 890 CL; D001575:Benzomorphans; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C041417:batrachotoxin receptor; D018698:Glutamic Acid; D014701:Veratridine