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

Despite the therapeutic relevance of delta-containing gamma-aminobutyric acid type A receptors (GABA(A)Rs) and the need for delta-selective compounds, the structural determinants for the mode and molecular site of action of delta-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 delta-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 alpha 4 beta 1 delta as mid-high nanomolar potency delta-selective allosteric modulators, displaying 6-16 times higher potency than DS2. Of these, 30 also displayed at least 60-fold selectivity for alpha 4 beta 1 delta over alpha 4 beta 1.2 receptor subtypes representing a potential tool for the selective characterization of delta-containing GABA(A)Rs in general.

Automated summary

Research on DS2 analogues revealed that substituents at the 5-position of the imidazopyridine core scaffold greatly affect delta-selectivity and pharmacological profile. Among them, analogue 30 showed at least 60-fold selectivity for the α4β1δ receptor subtype, indicating a potential tool for selective characterization of delta-containing GABA(A)Rs.