Pharmacological actions of oximino-propofol analogues at GABA(B) autoreceptors.
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-ditbutyl-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-diisopropylphenyl)-2-methyl-1-oximinopropane (compound 1), 1-[(3,5-ditbutyl-4-hydroxyphenyl)methyl]-1-oximinomethylcyclohexane (compound 3), 3-(3,5-ditbutyl-4-hydroxyphenyl)-1,2-diphenyl-1-oximinopropane (compound 4) and 4-(3,5-ditbutyl-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-ditbutyl-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-ditbutyl-4-hydroxyphenyl)methyl]-1-methyl-2-oximinocyclohexane (compound 7), 4-(3,5-ditbutyl-4-hydroxyphenyl)-3,3-dimethyl-2-oximinobutane (compound 8) and 4-(4-hydroxy-3,5-diisopropylphenyl)-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.
School of Dentistry, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
David A S
DA
Parker
Victor
V
Marino
Thomas
T
Sullivan
Jennifer
J
Ong
Jabbar
J
Khalafy
Mohammad
M
Badali
Mehdi
M
Rimaz
Rolf H
RH
Prager
D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D001418:Baclofen / Q000494:pharmacology; D004558:Electric Stimulation; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D019579:Neocortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology; D015742:Propofol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism*; D014316:Tritium / Q000032:analysis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D017660:Autoreceptors; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D009025:Morpholines; D010091:Oximes; D010636:Phenols; D018080:Receptors, GABA-B; D014316:Tritium; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; D015742:Propofol