Pharmacological actions of oximino-propofol analogues at GABAB autoreceptors

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dc.contributor.authorParker, D.
dc.contributor.authorMarino, V.
dc.contributor.authorSullivan, T.
dc.contributor.authorOng, J.
dc.contributor.authorKhalafy, J.
dc.contributor.authorBadali, M.
dc.contributor.authorRimaz, M.
dc.contributor.authorPrager, R.
dc.date.issued2011
dc.description.abstract1. 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.
dc.description.statementofresponsibilityDavid AS Parker, Victor Marino, Thomas Sullivan, Jennifer Ong, Jabbar Khalafy, Mohammad Badali, Mehdi Rimaz and Rolf H Prager
dc.identifier.citationClinical and Experimental Pharmacology and Physiology, 2011; 38(4):203-207
dc.identifier.doi10.1111/j.1440-1681.2011.05484.x
dc.identifier.issn1440-1681
dc.identifier.issn1440-1681
dc.identifier.orcidSullivan, T. [0000-0002-6930-5406]
dc.identifier.orcidOng, J. [0000-0002-0958-460X]
dc.identifier.urihttp://hdl.handle.net/2440/69911
dc.language.isoen
dc.publisherWiley-Blackwell Publishing Asia
dc.rights© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.
dc.source.urihttps://doi.org/10.1111/j.1440-1681.2011.05484.x
dc.subjectautoreceptors
dc.subjectbaclofen
dc.subjectGABA
dc.subjectGABAB receptors
dc.subjectrat brain slices.
dc.titlePharmacological actions of oximino-propofol analogues at GABAB autoreceptors
dc.typeJournal article
pubs.publication-statusPublished

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