HTS-based discovery and optimization of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor

HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of alpha 7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of a7 nAChRs. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

The high-throughput screening campaign of the corporate compound collection identified a novel oxalic acid diamide scaffold of alpha 7 nACh receptor positive allosteric modulators. The hit expansion led to the discovery of potent derivatives, with compound 55 demonstrating the most balanced physico-chemical and pharmacological profile. Docking studies showed an intersubunit binding site for the compounds, and compound 55 showed favorable cognitive enhancing effects in various tests, making it a lead compound for further optimization.