Pharmacological actions of oximino-propofol analogues at GABAB autoreceptors

1. GABA_B autoreceptors are a subclass of GABA_B 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 GABA_B 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 GABA_B autoreceptors.