Synthesis and evaluation of avermectin-imidazo[1,2-a]pyridine hybrids as potent GABA_A receptor modulators

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.