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

  • J Med Chem. 2021 Apr 22;64(8):4730-4743. doi: 10.1021/acs.jmedchem.0c02163.
Frederik Rostrup  1 ,  Christina B Falk-Petersen  1 ,  Kasper Harpso E  1 ,  Stine Buchleithner  1 ,  Irene Conforti  1 ,  Sascha Jung  2 ,  David E Gloriam  1 ,  Tanja Schirmeister  2 ,  Petrine Wellendorph  1 ,  Bente Fro Lund  1
Affiliations
  • 1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.
  • 2. Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Mainz D-55128, Germany.
PMID: 33847501 DOI: 10.1021/acs.jmedchem.0c02163
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.

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