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 α7 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...

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Published in:	European journal of medicinal chemistry Vol. 222; p. 113560
Main Authors:	Ledneczki, István, Horváth, Anita, Tapolcsányi, Pál, Éles, János, Molnár, Katalin Dudás, Vágó, István, Visegrády, András, Kiss, László, Szigetvári, Áron, Kóti, János, Krámos, Balázs, Mahó, Sándor, Holm, Patrik, Kolok, Sándor, Fodor, László, Thán, Márta, Kostyalik, Diána, Balázs, Ottilia, Vastag, Mónika, Greiner, István, Lévay, György, Lendvai, Balázs, Némethy, Zsolt
Format:	Journal Article
Language:	English
Published:	Elsevier Masson SAS 15-10-2021
Subjects:	Alpha 7 nicotinic acetylcholine receptor Cognitive enhancement High-throughput screening Positive allosteric modulation Structure-activity relationship High-throughput screening Cognitive enhancement Alpha 7 nicotinic acetylcholine receptor Positive allosteric modulation Structure-activity relationship
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Summary:	HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 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 α7 nAChRs. [Display omitted] •HTS campaign provided α7 nACh receptor positive allosteric modulators.•Elimination of the putatively mutagenic aromatic-amine building block.•Novel, aminomethylindole compound family without aromatic-amine building block identified.•Docking study revealed an intersubunit binding site.•Favorable cognitive enhancing profile in scopolamine-induced amnesia, in natural forgetting and in touch-screen tests.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0223-5234 1768-3254
DOI:	10.1016/j.ejmech.2021.113560