Pregnenolone sulfate analogues differentially modulate GABA_A receptor closed/desensitised states.

ABSTRACT:

Background and purpose

GABA_A receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate.

Experimental approach

New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C-21 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABA_A receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulatio

SUBMITTER: Mortensen M 

PROVIDER: S-EPMC10952582 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature