1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones: Novel AMPA receptor antagonists
1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones: Novel AMPA receptor antagonists
复制标题
DOI：
10.1021/jm960506l
复制
发表时间：
1997-04-11
影响因子：
7.3
通讯作者：
Chapman, AG
中科院分区：
文献类型：
--
作者：
Chimirri, A;DeSarro, G;Chapman, AG
我们以前的出版物(欧元。J. Pharmacol. 1995, 294, 411-422)报道了一些2,3-苯二氮卓类药物的初步化学和生物学研究，这些药物是1-（4-氨基苯基）4-甲基-7,8-（亚甲二氧基）- 5h -2,3-苯二氮卓类药物的类似物（1,GYKI 52466），已被证明具有显著的抗惊厥活性。本文报道了新型1-芳基-3,5-二氢- 4h -2,3-苯二氮杂平-4-酮的合成及其抗惊厥作用的评价。观察到的发现扩展了先前提出的这类抗惊厥药的结构-活性关系。DBA/2小鼠和瑞士小鼠分别用听觉刺激和戊四唑或最大电刺激诱发癫痫发作。氨基苯基-(38)和1-（3'-氨基苯基）-3,5-二氢-7,8-二甲氧基- 4h -2,3-苯二氮平-4- 1（39）是该系列中最活跃的化合物，在所有试验中都证明比1更有效。特别是听觉刺激引起的神经张力的ED（50）值分别为：导数38的12.6 mu mol/kg，导数39的18.3 mu mol/kg，导数1的25.3 mu mol/kg。需要更高的剂量来阻断最大电击和戊四唑引起的强直伸展。此外，这些化合物具有比化合物1更持久的抗惊厥作用，而且毒性更小。研究了新型2,3-苯二氮卓类药物对2-氨基-3-（3-羟基-5-甲基异恶唑-4-酰基）丙酸（AMPA）诱发的惊厥的抗惊厥活性与其对苯二氮卓受体（BZR）的亲和力之间的可能相关性。2,3-苯二氮卓类药物不影响[H-3]氟马西尼与BZR的结合，相反，它们的抗惊厥作用不被氟马西尼逆转。另一方面，2,3-苯二氮卓类药物拮抗AMPA和阿尼西坦引起的癫痫发作，与AMPA受体的参与一致。此外，衍生物38和化合物1均以非竞争方式显著降低豚鼠体外嗅觉皮质神经元中AMPA受体介导的膜电流。衍生物25和38-40不能取代n -甲基- d -天冬氨酸（NMDA）、AMPA/kainate或代谢性谷氨酸受体的特定配体。
Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of 1-(4-aminophenyl)4-methyl-7,8-(methylenedioxy)-5H-2,3- benzodiazepines (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. This paper describes the synthesis of new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluation of their anticonvulsant effects. The observed findings extend the structure-activity relationships previously suggested for this class of anticonvulsants. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. Aminophenyl)- (38) and 1-(3'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3- benzodiazepin-4-one (39), the most active compounds of the series, proved to be more potent than 1 in all tests employed. In particular, the ED(50) values against tonus evoked by auditory stimulation were 12.6 mu mol/kg for derivative 38, 18.3 mu mol/kg for 39, and 25.3 mu mol/kg for 1. Higher doses were necessary to block tonic extension induced both by maximal electroshock and by pentylenetetrazole. In addition these compounds exhibited anticonvulsant properties that were longer lasting than those of compound 1 and were less toxic. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsions induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and their affinities for benzodiazepine receptors (BZR). The 2,3-benzodiazepines did not affect the binding of [H-3]flumazenil to BZR, and conversely, their anticonvulsant effects were not reversed by flumazenil. On the other hand the 2,3-benzodiazepines antagonized seizures induced by AMPA and aniracetam in agreement with an involvement of the AMPA receptor. In addition, both the derivative 38 and the compound 1 markedly reduced the AMPA receptor-mediated membrane currents in guinea-pig olfactory cortical neurons in vitro in a noncompetitive manner. The derivatives 25 and 38-40 failed to displace specific ligands from N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutamate receptors.