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

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.