GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study

Psychopharmacology
Maja JohanssonTorbjörn Bäckström

Abstract

GR3027 is a novel small molecule GABA-A receptor-modulating steroid antagonist, which in non-clinical studies has shown promise for treatment of human disorders due to allosteric over-activation of GABA-A receptors by neurosteroids, such as allopregnanolone. We here studied its safety, pharmacokinetics, and ability to inhibit allopregnanolone effects in humans. Safety and pharmacokinetics were studied in healthy adult males receiving ascending single or multiple oral GR3027 vs. placebo. GR3027-mediated reversal of allopregnanolone effect on maximal saccadic eye velocity (SEV), and self-rated somnolence was studied in a double-blind, placebo-controlled, three-part cross-over study in which 3 or 30 mg oral GR3027 preceded 0.05 mg/kg of i.v. allopregnanolone. GR3027 was well tolerated, adverse events were generally mild and transient, and no dose-limiting toxicity or grade 3 adverse events were observed up to the highest single (200 mg) or multiple (100 mg every 12 h for 5 days) doses. The maximum concentration (Cmax) and systemic exposure (area under the plasma concentration-time curve from dose extrapolated to infinity [AUC0-∞] and/or AUC during the dosing interval [AUCτ]) varied linearly with dose; with dose-dependent accumulat...Continue Reading

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Citations

Jul 17, 2019·Bioorganic & Medicinal Chemistry Letters·Younggi Choi, Brian K Raymer
Aug 3, 2021·Journal of Neuroendocrinology·Torbjörn BäckströmMarie Bixo
Feb 6, 2019·Journal of Medicinal Chemistry·Quinn CoughlinDario Doller

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Methods Mentioned

BETA
sedation

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SPSS
Phoenix WinNonlin®
SAS®

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