De Sarro G, Chimirri A, McKernan R, Quirk K, Giusti P, De Sarro A
Institute of Pharmacology, School of Medicine, University of Reggio Calabria and Messina, Catanzaro, Italy.
Pharmacol Biochem Behav. 1997 Sep;58(1):281-9. doi: 10.1016/s0091-3057(96)00565-5.
The anticonvulsant properties of several 1,4-benzodiazepine and azirino[1,2-d][1,4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal (IP) administration in DBA/2 mice (a strain genetically susceptible to sound-induced seizures) and in Swiss mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a hemispheric Perspex dome or on seizures induced by administration of pentylenetetrazole. The 1,4-benzodiazepines were generally more potent than the related ABDZ derivatives. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. The impairment of locomotor performance following IP administration of these derivatives was also evaluated by means of the rotarod test. The rank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. The potency of various 1,4-benzodiazepines and ABDZs as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, ABDZs were active as anticonvulsants and inhibited [3H]flumazenil binding in the micromolar range. Radioligand binding studies carried out in stable cell lines demonstrated that none of the ABDZs tested showed a particular subtype specificity. The pharmacological actions of ABDZ4 and ABDZ5, which appeared to be the most potent ABDZs as anticonvulsants, were significantly reduced by treatment with flumazenil (8.24 mumol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced in DBA/2 mice by two beta-carbolines: methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6,6-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). Both ABDZ4 and ABDZ5 give better protection against seizures induced by beta-CCM than DMCM, suggesting a preferential action on the benzodiazepine receptor subtype BDZ1.
在DBA/2小鼠（一种对声音诱发癫痫具有遗传易感性的品系）和瑞士小鼠中腹腔注射给药后，研究了几种1,4 - 苯二氮䓬和氮杂环丙啶并[1,2 - d][1,4]苯二氮䓬（ABDZ）衍生物的抗惊厥特性。在单独置于半球形有机玻璃罩下的动物中，通过听觉刺激（109分贝，12 - 16千赫兹）诱发癫痫，或通过给予戊四氮诱发癫痫，评估抗惊厥效果。1,4 - 苯二氮䓬通常比相关的ABDZ衍生物更有效。抗惊厥活性的效力顺序为氟硝西泮＞地西泮＞匹那西泮＞ABDZ5＞ABDZ4＞普拉西泮＞哈拉西泮＞ABDZ1＞ABDZ3＞卡马西泮＞ABDZ6＞ABDZ2。还通过转棒试验评估了腹腔注射这些衍生物后对运动性能的损害。协调运动受损的效力顺序为匹那西泮＞氟硝西泮＞地西泮＞ABDZ5＞普拉西泮＞哈拉西泮＞ABDZ4＞ABDZ3＞ABDZ1＞卡马西泮＞ABDZ2 = ABDZ6。评估了各种1,4 - 苯二氮䓬和ABDZ作为特异性[³H]氟马西尼与小脑或皮质膜结合抑制剂的效力。一般来说，ABDZ作为抗惊厥药具有活性，并在微摩尔范围内抑制[³H]氟马西尼结合。在稳定细胞系中进行的放射性配体结合研究表明，所测试的ABDZ均未显示出特定的亚型特异性。作为抗惊厥药似乎最有效的ABDZ4和ABDZ5的药理作用，在用氟马西尼（8.24微摩尔/千克腹腔注射）治疗后显著降低，这表明苯二氮䓬机制明显参与了这些化合物或其代谢物的抗惊厥活性。还针对两种β - 咔啉：甲基 - β - 咔啉 - 3 - 羧酸甲酯（β - CCM）和甲基 - 6,6 - 二甲氧基 - 4 - 乙基 - β - 咔啉 - 3 - 羧酸甲酯（DMCM）在DBA/2小鼠中诱发的癫痫，评估了ABDZ4和ABDZ5的抗惊厥活性。ABDZ4和ABDZ5对β - CCM诱发的癫痫的保护作用均优于DMCM，这表明对苯二氮䓬受体亚型BDZ1具有优先作用。
