BIII-277-CL TS A POTENT AND SPECIFIC ION-CHANNEL BLOCKER OF THE NMDA RECEPTOR-CHANNEL

We determined the ability of a new benzomorphan derivative [2R-[2 alph a,3(R),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 [H-3]MK-801 binding from the NMDA rece ptor-channel complex in synaptosomal membrane preparations from rat br ain cortex (K-i = 4.49 nmol/l). It was much less effective at displaci ng [H-3]dihydromorphine, [H-3]naloxone and [H-3]ditolylguanidine bindi ng in similar membrane preparations: the Ki values were 3323, 8031 and 1017 nmol/l, respectively. BIII 277 CL did not exhibit any marked aff inities for a variety of other central neurotransmitter receptors. BII I 277 CL antagonized NMDA-induced [H-3]noradrenaline release (EC(50) = 1.7 mu mol/l) and NMDA-induced inhibition of protein synthesis in rat hippocampal dices (EC(50) = 3.0 mu mol/l). In mice, BIII 277 CL preve nted NMDA-induced lethality (ID50 = 0.54 mg/kg s.c.) and, as expected, also caused disturbances in motor coordination in the same dose range (ED(50) = 0.47 mg/kg s.c.). The duration of BIII 277 CL was much shor ter 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 unila teral occlusion of the middle cerebral artery. In summary, these resul ts indicate that BIII 277 CL is a potent and specific ion-channel bloc ker of the NMDA receptor-channel complex which could be used for the t reatment of acute thromboembolic stroke in humans.