Palmer G C, Stagnitto M L, Ray R K, Knowles M A, Harvey R, Garske G E
CNS Biology, Fisons Pharmaceuticals, Divisional R&D, Rochester, New York.
Epilepsia. 1993 Mar-Apr;34(2):372-80. doi: 10.1111/j.1528-1157.1993.tb02424.x.
Ten calcium channel blockers were evaluated in mice after intraperitoneal (i.p.) administration for prevention of seizures induced by various convulsants. The dihydropyridines (class II calcium antagonists, i.e., nisoldipine, nitrendipine, nicardipine, nifedipine, and nimodipine) selectively prevented seizures elicited by administration of pentylenetetrazol (PTZ), N-methyl-D,L-aspartate (NMDLA) and the dihydropyridine calcium channel agonist BAY K 8644. With regard to prevention of NMDLA-induced seizures and the subsequent mortality, these compounds were similar in potency to the noncompetitive NMDA receptor antagonist MK801. Unlike MK801 (IC50 = 0.014 microM), the dihydropyridines did not inhibit in vitro binding of MK801 to synaptic membrane fractions prepared from rat cerebrohippocampal tissue. The dihydropyridines did not influence seizures elicited by maximal electroshock (MES). Flunarizine (diphenyl-alkylamine, class IV) was selectively active in the MES test, considerably less potent against NMDLA-induced convulsions/mortality, exhibited weak noncompetitive NMDA antagonism in vitro (IC50 = 28 microM), and was inactive in the PTZ and BAY K 8644 testing paradigms. Diltiazem, a class III benzothiazepine, possessed relatively weak broad spectra of activity against MES, PTZ, NMDLA, and BAY K 8644 test situations. It was inactive in vitro as a noncompetitive NMDA antagonist. The class I compound verapamil (phenylalkylamine) displayed only moderate inhibition of NMDLA-evoked seizures/mortality. Prenylamine (class V) was moderately active against convulsions produced by MES and NMDLA while retaining a degree (IC50 = 16 microM) of noncompetitive NMDA antagonism. Lidoflazine (class VI) was inactive in all tests. The Ca2+ channel blockers and MK801 were inconsistent in their ability to prevent bicuculline (BIC)-elicited convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)
对10种钙通道阻滞剂进行腹腔注射后在小鼠体内进行评估，以预防由各种惊厥剂诱发的癫痫发作。二氢吡啶类（II类钙拮抗剂，即尼索地平、尼群地平、尼卡地平、硝苯地平和尼莫地平）选择性地预防了由戊四氮（PTZ）、N-甲基-D，L-天冬氨酸（NMDLA）和二氢吡啶钙通道激动剂BAY K 8644诱发的癫痫发作。就预防NMDLA诱发的癫痫发作及随后的死亡率而言，这些化合物在效力上与非竞争性NMDA受体拮抗剂MK801相似。与MK801（IC₅₀ = 0.014微摩尔）不同，二氢吡啶类在体外不抑制MK801与从大鼠脑海马组织制备的突触膜组分的结合。二氢吡啶类不影响最大电休克（MES）诱发的癫痫发作。氟桂利嗪（二苯基烷基胺，IV类）在MES试验中具有选择性活性，对NMDLA诱发的惊厥/死亡率的效力相当低，在体外表现出弱的非竞争性NMDA拮抗作用（IC₅₀ = 28微摩尔），并且在PTZ和BAY K 8644测试范式中无活性。地尔硫䓬，一种III类苯并硫氮䓬，对MES、PTZ、NMDLA和BAY K 8644测试情况具有相对较弱的广谱活性。它在体外作为非竞争性NMDA拮抗剂无活性。I类化合物维拉帕米（苯烷基胺）仅对NMDLA诱发的癫痫发作/死亡率有中度抑制作用。普尼拉明（V类）对MES和NMDLA产生的惊厥具有中度活性，同时保留一定程度（IC₅₀ = 16微摩尔）的非竞争性NMDA拮抗作用。利多氟嗪（VI类）在所有测试中均无活性。钙通道阻滞剂和MK801在预防荷包牡丹碱（BIC）诱发的惊厥方面的能力不一致。（摘要截短于250字）
