Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex. 853 Nov 6

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.
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PMID:Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL. 1078 Nov 2