The γ-aminobutyric acid type A (GABA_A) receptors are pentameric transmembrane protein complexes. They have attracted extensive attention from the scientific community due to their significant pharmacological potential. Here we report the first synthesis of avermectin–imidazo[1,2-a]pyridine hybrids promising as GABA_A receptor positive allosteric modulators (PAMs). An efficient multi-step protocol was elaborated for the installation of the 6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine pendant to the Avermectin B_1a and Ivermectin skeletons through a linker. A variety of linkers were used in order to study the effect of disturbances in the hybrid structure on the GABA_A receptor affinity. In vitro experiments showed that the lead compounds exhibited high potency (IC₅₀ = 207 and 359 nM) for binding at the benzodiazepine site of GABA_A receptors. In silico studies suggest that the hybrids are able to bind at the Ivermectin binding site of the GABA_A receptor. The functional properties of the highest-affinity hybrid (compound 15e) as GABA_AR PAM were evaluated by patch-clamp electrophysiological recordings of GABA-mediated currents in rat cerebellar Purkinje neurons. The results obtained suggest that the potentiating effect of hybrid compound 15e is due to its interaction both with benzodiazepine- and Ivermectin-binding sites of GABA_ARs. Drug-induced behavioral responses in adult zebrafish for hybrids correlate with an alternative mode of action of avermectin and imidazo[1,2-a]pyridine pharmacophores. The investigation of avermectin–imidazo[1,2-a]pyridine hybrid molecules with activity as GABA_A receptor modulators is important for the discovery of safe and effective drugs for the treatment of neurological disorders and pest control agents.

γ-氨基丁酸 A 型 (GABA _A ) 受体是五聚体跨膜蛋白复合物。由于其显着的药理潜力，它们引起了科学界的广泛关注。在这里，我们报告了阿维菌素-咪唑并[1,2- a ]吡啶杂化物的首次合成，有望作为 GABA _A受体正变构调节剂 (PAMs)。详细阐述了一种有效的多步骤方案，用于通过连接器将 6-甲基-2-(对甲苯基)咪唑并[1,2 - a ]吡啶侧基安装到阿维菌素 B _1a和伊维菌素骨架上。为了研究杂化结构中的干扰对 GABA _{A的影响，使用了多种接头}受体亲和力。体外实验表明，先导化合物在 GABA _A受体的苯二氮卓位点结合表现出高效（IC ₅₀  = 207 和 359 nM） 。计算机研究表明，杂交体能够在 GABA _A受体的伊维菌素结合位点结合。通过大鼠小脑浦肯野神经元中 GABA 介导的电流的膜片钳电生理记录来评估作为 GABA _A R PAM的最高亲和力杂种 (化合物15e ) 的功能特性。所得结果表明杂化化合物15e的增强作用是由于它与 GABA _A Rs 的苯二氮卓和伊维菌素结合位点的相互作用。成年斑马鱼对杂种的药物诱导行为反应与阿维菌素和咪唑并[1,2- a ]吡啶药效团的另一种作用模式相关。_{研究具有作为 GABA A}受体调节剂活性的阿维菌素-咪唑并[1,2- a ]吡啶杂化分子对于发现治疗神经系统疾病和害虫控制剂的安全有效药物具有重要意义。