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Updated: Jan 7, 2026

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Discovery of an In Vitro and In Vivo Potent Nicotinic α7 Positive Allosteric Modulator Clinical Candidate Molecule
István Ledneczki1, Pál Tapolcsányi1, Eszter Gábor1
1Gedeon Richter Plc., 19-21 Gyömrői út, Budapest H-1103, Hungary.
Abstract:
While identifying α7 nACh receptor positive allosteric modulators, a novel scaffold (1,1-dioxo-thiadiazine core) emerged from our HTS campaign, exhibiting unusually low lipophilicity compared to other screening hits. During the hit-to-lead optimization, the importance of different structural elements was evaluated. Upon combination of the best building blocks, first a lead molecule (25), then after a subsequent lead optimization, a clinical candidate compound (51, RGH-857) was identified. Having the most balanced physicochemical and in vitro pharmacological profile combined with significant in vivo efficacy in models of scopolamine-induced amnesia and natural forgetting, our results suggest that cognitive enhancement through the positive modulation of α7 nAChRs can be a viable approach to targeting cognitive decline.
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