Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors

Frederik Rostrup, Christina B. Falk-petersen, Kasper Harpsøe, Stine Buchleithner, Irene Conforti, Sascha Jung, David E. Gloriam, Tanja Schirmeister, Petrine Wellendorph, Bente Frølund

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1 Citationer (Scopus)

Abstract

Despite the therapeutic relevance of δ-containing γ-aminobutyric acid type A receptors (GABAARs) and the need for δ-selective compounds, the structural determinants for the mode and molecular site of action of δ-selective positive allosteric modulator imidazo[1,2-a]pyridine DS2 remain elusive. To guide the quest for insight, we synthesized a series of DS2 analogues guided by a structural receptor model. Using a fluorescence-based fluorometric imaging plate reader membrane potential assay, we found that the δ-selectivity and the pharmacological profile are severely affected by substituents in the 5-position of the imidazopyridine core scaffold. Interestingly, the 5-methyl, 5-bromo, and 5-chloro DS2 analogues, 30, 35, and 36, were shown to be superior to DS2 at α4β1δ as mid-high nanomolar potency δ-selective allosteric modulators, displaying 6–16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for α4β1δ over α4β1γ2 receptor subtypes representing a potential tool for the selective characterization of δ-containing GABAARs in general.
OriginalsprogEngelsk
TidsskriftJournal of Medicinal Chemistry
Vol/bind64
Udgave nummer8
Sider (fra-til)4730-4743
Antal sider14
ISSN0022-2623
DOI
StatusUdgivet - 22 apr. 2021

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