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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C\u201021 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABA<jats:sub>A<\/jats:sub> receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>All seven analogues retained a negative allosteric modulatory capability whilst exhibiting diverse potencies. Interestingly, we observed differential effects on GABA current decay by compounds incorporating either a six\u2010 (compound <jats:bold>5<\/jats:bold>) or five\u2010membered heterocyclic ring (compound <jats:bold>6<\/jats:bold>) on C\u201021, which was independent of their potencies as inhibitors. We propose that differences in molecular charges, and the targeted binding of analogues to specific states of the GABA<jats:sub>A<\/jats:sub> receptor, are the most likely cause of the distinctive functional profiles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our findings reveal that heterocyclic addition to inhibitory neurosteroids not only affected their potency and macroscopic efficacy but also affected innate receptor mechanisms that underlie desensitisation. Acute modulation of macroscopic desensitisation will determine the degree and duration of GABA inhibition, which are vital for the integration of neural circuit activity. Discovery of this form of modulation could present an opportunity for next\u2010generation GABA<jats:sub>A<\/jats:sub> receptor drug design and development.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16143","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T08:32:24Z","timestamp":1684312344000},"page":"2482-2499","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pregnenolone sulfate analogues differentially modulate GABA<sub>A<\/sub> receptor closed\/desensitised states"],"prefix":"10.1111","volume":"180","author":[{"given":"Martin","family":"Mortensen","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology University College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Drug Design and Pharmacology, Faculty of Health and 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