We have synthesized a new benzomorphan derivative, 2R-[2␣,3(S*),6␣]-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-20␣-benzoate from neurotoxin receptor site 2 of the 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 ␣ subunits and shifted steadystate 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 M). Point mutations F1764A and Y1771A in transmembrane segment S6 in domain IV of the ␣ 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 mg͞kg 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 usedependent Na ؉ channel blocker that protects brain tissue from the deleterious effects of focal cerebral ischemia in rodents.

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We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified N-substituents and determined their ability to antagonize the N-methyl-D-aspartate (NMDA) receptor-channel complex in vitro and in vivo. The ability of the compounds to displace [3H]-MK-801 from the channel site of the NMDA receptor in rat brain synaptosomal membranes and to inhibit NMDA-induced lethality in mice was compared with their ability to bind to the mu opioid receptor. Examination of structure-activity relationships showed that the absolute stereochemistry is critically important for differentiating these two effects. (-)-1R,9 beta,2"S-enantiomers exhibited a higher affinity for the NMDA receptor-channel complex than for the mu opioid receptor. The aromatic hydroxy function was also found to influence the specificity of the compounds. Shift of the hydroxy group from the 2'-position to the 3'-position significantly increased the affinity for the NMDA receptor-channel complex and considerably reduced the affinity for the mu opioid receptor. From this series of 6,7-benzomorphan derivatives, the compound 15cr.HCl [(2R)-[2 alpha, 3(R*),6 alpha]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)-6,11,11-trimethyl -2,6-methano-3-benzazocin-9-ol hydrochloride] was chosen as the optimum candidate for further pharmacological investigations.

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