Variations on a scaffold - Novel GABAA receptor modulators

GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain—Can the Promiscuity Code Be Cracked?

“…This is also supported by density functional theory (DFT) calculations, which show that an intramolecular hydrogen bond stabilizes the molecule by 11.2 kcal/mol (see Appendix A, Figure A1), providing an explanation for the low acidity observed. Additionally, our previously reported crystal structure [12] While modulation in the binary subunit combinations α1β2 and α1β3 does not reach saturation up to 30 µM, α1β3γ2cct and α1β1 receptors show a typical sigmoidal dose response curve (Figure 4a). The observed β isoform profile could reflect interactions with either site 2 at the extracellular domain's α+/β− interface or site 3 at the transmembrane domain's β+/α− interface.…”

“…In our previous work [12], we published a library of novel modulators derived from the modification of the scaffold of pyrazoloquinolinones (Figure 2). In this follow-up study, we aimed to investigate the binding sites of these novel structures.…”

“…The indole derivative MTI163 was synthesized as previously described [12]. DCBS192 was synthesized according to a previously reported route [13,15].…”

“…This is also supported by density functional theory (DFT) calculations, which show that an intramolecular hydrogen bond stabilizes the molecule by 11.2 kcal/mol (see Appendix A, Figure A1), providing an explanation for the low acidity observed. Additionally, our previously reported crystal structure [12] displays the molecule in the same conformation as calculated as the most stable one and hence this conformer was used for docking. For etomidate, we have no indication to select a particular conformer, it was thus docked as a fully flexible ligand.…”

“…In a previous work, we identified a series of indole derivatives, sharing pharmacophore features with pyrazoloquinolinones (PQs), as GABA A modulators (Figure 2a) [12]. PQs are known to bind with high affinity at the BZ site (site 1) and to modulate the receptors via the interaction with a second binding site of the ECD, at the interface between α+ and β− (site 2) [13].…”