In the current study, a series of novel 1,2,4-triazol-3-amine derivatives were designed, synthesized, and biologically evaluated in vivo for their anticonvulsant and hypnotic effects in the pentylenetetrazole (PTZ)-induced seizures, maximal electroshock (MES)-induced seizures, and pentobarbital-induced sleeping tests. Furthermore, the possible side effects of the most potent compounds on the memory, motor coordination, and muscle strength were evaluated in passive avoidance, rotarod, and grip strength tests, respectively. The designed compounds with the main benzodiazepine pharmacophores including aromatic ring and proton accepting group completely mimiced the structure of zolpidem as an α1-selective agonist of GABA_A receptor. Compounds 5c (ED₅₀ ≈ 52.5 mg/kg) and 5 g (ED₅₀ ≈ 16.5 mg/kg) in the PTZ test were the most potent compounds among the designed compounds. In the MES test, the observed ED_50s for compounds 5c and 5 g were reduced to around 11.8 mg/kg and 10.5 mg/kg, respectively. The considerable hypnotic effect in a dose-dependent manner was observed following the administration of newly synthesized compounds. In all experiments administration of flumazenil as an antagonist of benzodiazepines receptor fully antagonized observed effects which indicated the involvement of GABA_A receptors. Since there was no negative effect on memory, motor coordination, and muscle strength following the administration of compounds 5c and 5g as the most potent compounds, it could be concluded that the novel compounds most likely act through α1-containing GABA_A receptors and possess no affinity for α5-containing receptors. The newly designed compounds could be considered as leading compounds in synthesizing novel GABA_A receptor agonists with minimum side effects.

在目前的研究中，一系列新颖的1,2,4-三唑-3-胺衍生物的设计，合成，和生物学评价在体内为它们在抗惊厥戊四和催眠作用（PTZ）诱发的癫痫发作，最大电（ MES引起的癫痫发作和戊巴比妥引起的睡眠试验。此外，分别在被动回避，轮转和握力测试中评估了最有效化合物对记忆，运动协调和肌肉力量可能产生的副作用。设计的化合物具有主要的苯并二氮杂药效团，包括芳香环和质子接受基团，完全模拟了唑吡坦的结构，作为GABA _A受体的α1选择性激动剂。化合物5c（ED ₅₀≈52.5毫克/千克）和5g（ED ₅₀ ≈16.5毫克/千克）在PTZ测试是所设计的化合物中最有效的化合物。在MES测试中，观察到的化合物5c和5 g的ED _50s分别降至约11.8 mg / kg和10.5 mg / kg。在施用新合成的化合物后，观察到剂量依赖性的催眠作用。在所有实验中，氟马西尼作为苯二氮卓类受体的拮抗剂的给药完全拮抗了观察到的作用，这表明了GABA _A的参与受体。由于服用最有效的化合物5c和5g对记忆，运动协调和肌肉力量没有负面影响，因此可以得出结论，新化合物很可能通过含α1的GABA _A受体发挥作用，并且不具有对含α5受体的亲和力。新设计的化合物可以被认为是合成具有最小副作用的新型GABA _A受体激动剂的主要化合物。