Structure-Guided Computational Methods Predict Multiple Distinct Binding Modes for Pyrazoloquinolinones in GABA_A Receptors.

ABSTRACT: Pyrazoloquinolinones (PQs) are a versatile class of GABA_A receptor ligands. It has been demonstrated that high functional selectivity for certain receptor subtypes can be obtained by specific substitution patterns, but so far, no clear SAR rules emerge from the studies. As is the case for many GABA_A receptor targeting chemotypes, PQs can interact with distinct binding sites on a given receptor pentamer. In pentamers of αβγ composition, such as the most abundant α1β2γ2 subtype, many PQs are high affinity binders of the benzodiazepine binding site at the extracellular α+/γ2- interfaces. There they display a functionally near silent, flumazenil-like allosteric activity. More recently, interactions with extracellular α+/β- interfaces have been investigated, where strong p

SUBMITTER: Fabjan J 

PROVIDER: S-EPMC7844064 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature