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Pharmacological actions of oximino‐propofol analogues at GABA B autoreceptors
Author(s) -
Parker David AS,
Marino Victor,
Sullivan Thomas,
Ong Jennifer,
Khalafy Jabbar,
Badali Mohammad,
Rimaz Mehdi,
Prager Rolf H
Publication year - 2011
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2011.05484.x
Subject(s) - gabab receptor , chemistry , autoreceptor , baclofen , gabaa receptor , agonist , stimulation , stereochemistry , gabaergic , receptor , pharmacology , biochemistry , endocrinology , biology
Summary 1. GABA B autoreceptors are a subclass of GABA B receptors that inhibit the release of [ 3 H]GABA from GABAergic nerve terminals. Baclofen is an agonist that reduces [ 3 H]GABA, whilst the antagonist (+)‐(S)‐5,5‐dimethylmorpholinyl‐2‐acetic acid (Sch 50911) enhances [ 3 H]GABA release in electrically‐stimulated rat neocortical brain slices preloaded with [ 3 H]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‐di t butyl‐4‐hydroxyphenyl)‐2,2‐dimethyl‐1‐oximinopropane (compound 2), at 10 μmol/L had little effect on the stimulation‐induced overflow of [ 3 H]GABA when superfused alone, but when superfused in the presence of baclofen (2 μmol/L) inhibited the overflow of [ 3 H]GABA. These effects were reversed by Sch 50911 (10 μmol/L). Although compounds 1‐(4‐chlorophenyl)‐3‐(4‐hydroxy‐3,5‐di iso propylphenyl)‐2‐methyl‐1‐oximinopropane (compound 1), 1‐[(3,5‐di t butyl‐4‐hydroxyphenyl)methyl]‐1‐oximinomethylcyclohexane (compound 3), 3‐(3,5‐di t butyl‐4‐hydroxyphenyl)‐1,2‐diphenyl‐1‐oximinopropane (compound 4) and 4‐(3,5‐di t butyl‐4‐hydroxyphenyl)‐3‐methyl‐2‐oximinobutane (compound 5) (each at 10 μmol/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‐di t butyl‐4‐hydroxyphenyl)‐1‐(4‐chlorophenyl)‐2‐methyl‐1‐oximinopropane (compound 6) (10 μmol/L), acted as an agonist as it inhibited the release of [ 3 H]GABA by 32% (EC 50 of 3.3 μmol/L), an effect reversed by Sch 50911 (10 μmol/L). The other compounds, 1‐[(3,5‐di t butyl‐4‐hydroxyphenyl)methyl]‐1‐methyl‐2‐oximinocyclohexane (compound 7), 4‐(3,5‐di t butyl‐4‐hydroxyphenyl)‐3,3‐dimethyl‐2‐oximinobutane (compound 8) and 4‐(4‐hydroxy‐3,5‐di iso propylphenyl)‐3,3‐dimethyl‐2‐oximinobutane (compound 9) (each at 10 μmol/L), were inactive. 4. These findings indicate that this series of compounds show different modes of activity at GABA B autoreceptors.