We determined the ability of a new
benzomorphan derivative [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 (
BIII 277 CL) to inhibit the
N-methyl-D-aspartic acid (
NMDA) receptor-channel complex in vitro and in vivo.
BIII 277 CL potently displaced [3H]
MK-801 binding from the
NMDA receptor-channel complex in synaptosomal membrane preparations from rat brain cortex (Ki = 4.49 nmol/l). It was much less effective at displacing [3H]
dihydromorphine, [3H]
naloxone and [3H]ditolyguanidine binding in similar membrane preparations: the Ki values were 3323, 8031 and 1017 nmol/l, respectively.
BIII 277 CL did not exhibit any marked affinities for a variety of other central
neurotransmitter receptors.
BIII 277 CL antagonized
NMDA-induced [3H]
noradrenaline release (EC50 = 1.7 mumol/l) and
NMDA-induced inhibition of
protein synthesis in rat hippocampal slices (EC50 = 3.0 mumol/l). In mice,
BIII 277 CL prevented
NMDA-induced lethality (ID50 = 0.54 mg/kg s.c.) and, as expected, also caused disturbances in motor coordination in the same dose range (ED50 = 0.47 mg/kg s.c.). The duration of
BIII 277 CL was much shorter than than of (+)
MK-801 in both tests. Finally,
BIII 277 CL (0.3 mg/kg s.c. 5 times over 24 h) reduced the cortical
infarct area in mice that had been subjected previously to focal
cerebral ischemia by unilateral occlusion of the middle cerebral artery. In summary, these results indicate that
BIII 277 CL is a potent and specific
ion-channel blocker of the
NMDA receptor-channel complex which could be used for the treatment of acute thromboembolic
stroke in humans.