Synthesis of GABAA receptor agonists and evaluation of their α-subunit selectivity and orientation in the GABA binding site

Michaela Jansen, Holger Rabe, Axelle Strehle, Sandra Dieler, Fabian Debus, Gerd Dannhardt, Myles H. Akabas, Hartmut Lüddens

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Drugs used to treat various disorders target GABAA receptors. To develop α subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [3H]muscimol binding and in patch-clamp experiments with heterologously expressed GABAA αiβ 3γ2 receptors (i = 1-6). The effects of 5-aminomethyl-3H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all α subunit isoforms. 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-one 5a and 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-thione 6a were weak agonists at α2-, α3-, and α5-containing receptors. When coapplied with GABA, they were antagonistic in α2-, α4-, and α6-containing receptors and potentiated α3-containing receptors. 6a protected GABA binding site cysteine-substitution mutants α1F64C and α1S68C from reacting with methanethiosulfonate-ethylsulfonate. 6a specifically covalently modified the α1R66C thiol, in the GABA binding site, through its oxadiazolethione sulfur. These results demonstrate the feasibility of synthesizing α subtype selective GABA mimetic drugs.

Original languageEnglish (US)
Pages (from-to)4430-4448
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number15
StatePublished - Aug 14 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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