Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII890CL

We have synthesized a new benzomorphan derivative, 2R-[2 alpha,3(S*),6 alph a]-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 [H- 3]batrachotoxinin A-20 alpha-benzoate from neurotoxin receptor site 2 of th e Na+ channel in rat brain synaptosomes (IC50 = 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 or subunits an d shifted steady-state inactivation curves to more negative potentials. The IC50 value for the inactivated Na+ channel was much lower (77 nM) than for Na+ channels in the resting state (18 mu M) Point mutations F1764A and Y17 71A in transmembrane segment S6 in domain IV of the alpha subunit reduced t he voltage- and frequency-dependent block, findings which suggest that BIII 890 CL binds to the local anesthetic receptor site in the pore, BIII 890 C L inhibited veratridine-induced glutamate release in brain slices, as well as glutamate release and neurotoxicity in cultured cortical neurons. BIII 8 90 CL (3-30 mg/kg s,c.) reduced lesion size in mice and rats when administe red 5 min after permanent focal cerebral ischemia at doses that did not imp air motor coordination. In contrast to many other agents, BIII 890 CL was n europrotective in both cortical and subcortical regions of the rat brain. O ur results demonstrate that BIII 890 CL is a potent, selective, and highly use-dependent Na+ channel blocker that protects brain tissue from the delet erious effects of focal cerebral ischemia in rodents.