Pharmacological actions of oximino-propofol analogues at GABAB autoreceptors

David As Parker, Victor Marino, Thomas Sullivan, Jennifer Ong, Jabbar Khalafy, Mohammad Badali, Mehdi Rimaz, Rolf H. Prager

Research output: Contribution to journalArticle

2 Citations (Scopus)


1. GABAB autoreceptors are a subclass of GABAB receptors that inhibit the release of [3H]GABA from GABAergic nerve terminals. Baclofen is an agonist that reduces [3H]GABA, whilst the antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911) enhances [3H]GABA release in electrically-stimulated rat neocortical brain slices preloaded with [3H]GABA. Here, the pharmacological actions of a series of compounds derived from the positive allosteric modulator, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930), were examined on GABAB autoreceptors. 2. The compound, 3-(3,5-ditbutyl-4-hydroxyphenyl)-2,2-dimethyl-1-oximinopropane (compound2), at 10μmol/L had little effect on the stimulation-induced overflow of [3H]GABA when superfused alone, but when superfused in the presence of baclofen (2μmol/L) inhibited the overflow of [3H]GABA. These effects were reversed by Sch 50911 (10μmol/L). Although compounds 1-(4-chlorophenyl)-3-(4-hydroxy-3,5-diisopropylphenyl)-2-methyl-1-oximinopropane (compound1), 1-[(3,5-ditbutyl-4-hydroxyphenyl)methyl]-1-oximinomethylcyclohexane (compound3), 3-(3,5-ditbutyl-4-hydroxyphenyl)-1,2-diphenyl-1-oximinopropane (compound4) and 4-(3,5-ditbutyl-4-hydroxyphenyl)-3-methyl-2-oximinobutane (compound5) (each at 10μmol/L) tended to reduce the stimulation-induced overflow in the presence of baclofen, an effect reversed by Sch 50911, their status as modulators is not confirmed in the present study. 3. Another derivative, 3-(3,5-ditbutyl-4-hydroxyphenyl)-1-(4-chlorophenyl)-2-methyl-1-oximinopropane (compound6) (10μmol/L), acted as an agonist as it inhibited the release of [3H]GABA by 32% (EC50 of 3.3μmol/L), an effect reversed by Sch 50911 (10μmol/L). The other compounds, 1-[(3,5-ditbutyl-4-hydroxyphenyl)methyl]-1-methyl-2-oximinocyclohexane (compound7), 4-(3,5-ditbutyl-4-hydroxyphenyl)-3,3-dimethyl-2-oximinobutane (compound8) and 4-(4-hydroxy-3,5-diisopropylphenyl)-3,3-dimethyl-2-oximinobutane (compound9) (each at 10μmol/L), were inactive. 4. These findings indicate that this series of compounds show different modes of activity at GABAB autoreceptors.

Number of pages5
JournalClinical and Experimental Pharmacology and Physiology
Issue number4
Publication statusPublished - 1 Apr 2011
Externally publishedYes


  • Autoreceptors
  • Baclofen
  • GABA
  • GABA receptors
  • Rat brain slices

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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