TY - JOUR
T1 - Structural Determinants for the Mode of Action of Imidazopyridine DS2 at δ-Containing γ-Aminobutyric Acid Type A Receptors
AU - Rostrup, Frederik
AU - Falk-petersen, Christina B.
AU - Harpsøe, Kasper
AU - Buchleithner, Stine
AU - Conforti, Irene
AU - Jung, Sascha
AU - Gloriam, David E.
AU - Schirmeister, Tanja
AU - Wellendorph, Petrine
AU - Frølund, Bente
PY - 2021/4/22
Y1 - 2021/4/22
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jmedchem.0c02163
DO - 10.1021/acs.jmedchem.0c02163
M3 - Journal article
C2 - 33847501
VL - 64
SP - 4730
EP - 4743
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 8
ER -