Carter A J, Grauert M, Pschorn U, Bechtel W D, Bartmann-Lindholm C, Qu Y, Scheuer T, Catterall W A, Weiser T
Departments of Central Nervous System Research, Boehringer Ingelheim Pharma KG, 55216 Ingelheim am Rhein, Germany.
Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4944-9. doi: 10.1073/pnas.040577097.
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.
我们合成了一种新的苯并吗啡烷衍生物,2R-[2α,3(S*),6α]-1,2,3,4,5,6-六氢-6,11,11-三甲基-3-[2-(苯基甲氧基)丙基]-2,6-亚甲基-3-苯并氮杂环辛-10-醇盐酸盐(BIII 890 CL),它能将大鼠脑突触体中Na(+)通道神经毒素受体位点2上的[(3)H]蟾酥毒素A-20α-苯甲酸酯置换下来(IC(50)=49 nM),但对其他65种受体和离子通道仅表现出低亲和力。BIII 890 CL抑制转染了IIA型Na(+)通道α亚基的细胞中的Na(+)通道,并使稳态失活曲线向更负的电位移动。失活的Na(+)通道的IC(50)值(77 nM)比静息状态下的Na(+)通道(18 μM)低得多。α亚基结构域IV中跨膜片段S6的点突变F1764A和Y1771A降低了电压和频率依赖性阻滞,这些结果表明BIII 890 CL与孔道中的局部麻醉药受体位点结合。BIII 890 CL抑制脑片中藜芦碱诱导的谷氨酸释放,以及培养皮层神经元中的谷氨酸释放和神经毒性。在永久性局灶性脑缺血5分钟后,以不损害运动协调的剂量皮下注射BIII 890 CL(3 - 30 mg/kg)可减小小鼠和大鼠的损伤大小。与许多其他药物不同,BIII 890 CL在大鼠脑皮质和皮质下区域均具有神经保护作用。我们的结果表明,BIII 890 CL是一种强效、选择性且高度使用依赖性的Na(+)通道阻滞剂,可保护脑组织免受啮齿动物局灶性脑缺血的有害影响。