2. Academic Validation
  3. Spiro Hydantoins Can Reverse the Action of Positive Allosteric Modulators on GABAARs

Spiro Hydantoins Can Reverse the Action of Positive Allosteric Modulators on GABAARs

  • ACS Med Chem Lett. 2025 Sep 30;16(10):2078-2083. doi: 10.1021/acsmedchemlett.5c00499.
Dimosthenis A Koinas 1,  Xiaojuan Zhou 2,  Karol S Bruzik 1,  Keith W Miller 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Illinois Chicago, 833 South Wood Street, M/C 781, Chicago, Illinois 60612-7231, United States.
  • 2 Department of Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts 02114, United States.
PMID: 41089475 DOI: 10.1021/acsmedchemlett.5c00499
Abstract

GABAARs are the most abundant inhibitory neuroreceptors. Drugs that enhance their action are used to treat epilepsy, anxiety, and Other conditions. Benzodiazepines can exert a range of allosteric interactions from positive to negative, but they only act on γ-subunit containing GABAARs. Agents acting in the transmembrane domain can interact with a wider range of GABAARs, but they exert only positive allosteric actions, and their therapeutic actions are often limited by sedation because their binding sites are the same as those used by general anesthetics. Consequently, their therapeutic action is limited by sedation. We report the synthesis and pharmacological evaluation of several novel spiro-hydantoins that do not modulate orthosteric agonist binding but do reverse the positive allosteric action of agents acting in the transmembrane domain. The reversal action occurs in the low micromolar range and is α-subunit dependent with action on α3β3γ2 receptors occurring at concentrations as low as 200 nM.

Keywords

Allosteric modulators; Anesthetic; GABAAR; Hydantoin; Reversal agent.

Figures
Products