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GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umecrine Cognition AB, Karolinska Institutet Science Park, Fogdevreten 2, SE-171 65 Solna, Sweden.
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2018 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 235, no 5, p. 1533-1543Article in journal (Refereed) Published
Abstract [en]

RATIONALE: 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.

METHODS: 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.

RESULTS: ]) varied linearly with dose; with dose-dependent accumulation ratios of 1.3-1.6. Allopregnanolone decreased SEV and induced somnolence in most, but not all subjects. By predefined analyses, 30 mg GR3027 significantly inhibited allopregnanolone-induced decrease in SEV (p = 0.03); 3 and 30 mg GR3027 non-significantly inhibited allopregnanolone-induced sedation. By post hoc analyses restricted to subjects with allopregnanolone-induced changes and the time period over which they occurred, GR3027 dose dependently inhibited allopregnanolone-induced decrease in SEV (p = 0.04 at 30 mg, non-significant at 3 mg) and allopregnanolone-induced sedation (p = 0.01/0.05 at 3/30 mg doses).

CONCLUSION: Oral GR3027 mitigates inhibition of brain function induced by allopregnanolone at doses which are clinically well tolerated and associated with linear pharmacokinetics.

Place, publisher, year, edition, pages
Springer, 2018. Vol. 235, no 5, p. 1533-1543
Keywords [en]
Allopregnanolone, Clinical trial, GR3027, Saccadic eye movement, Sedation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-148340DOI: 10.1007/s00213-018-4864-1ISI: 000431034400018PubMedID: 29492615OAI: oai:DiVA.org:umu-148340DiVA, id: diva2:1212935
Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2018-10-29Bibliographically approved

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