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Affinities of barbiturates for the GABA-receptor complex and A1 adenosine receptors: a possible explanation of their excitatory effects

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Summary

The effects of barbiturates on the GABA-receptor complex and the A1 adenosine receptor were studied. At the GABA-receptor complex the barbiturates inhibited the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPT) and enhanced the binding of [3H]diazepam. Kinetic and saturation experiments showed that both effects were allosteric. Whereas all barbiturates caused complete inhibition of [35S]TBPT binding, they showed varying degrees of maximal enhancement of [3H]diazepam binding; (±)methohexital was identified as the most efficacious compound for this enhancement. At the A1 adenosine receptor all barbiturates inhibited the binding of [3H]N6-phenylisopropyladenosine ([3H]PIA) in a competitive manner. The comparison of the effects on [3H]diazepam and [3H]PIA binding showed that excitatory barbiturates interact preferentially with the A1 adenosine receptor, and sedative/anaesthetic barbiturates with the GABA-receptor complex. It is speculated that the interaction with these two receptors might be the basis of the excitatory versus sedative/anaesthetic properties of barbiturates.

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Abbreviations

GABA:

γ-aminobutyric acid

TBPT:

t-butylbicyclophosphorothionate 1073

DMBB:

5-(1,3-dimethyl)butyl-5-ethylbarbituric acid

MCB:

N-methyl-5-(1-cyclohexen-1-yl)-5-ethylbarbituric acid

MPPB:

N-methyl-5-phenyl-5-propylbarbituric acid

PIA:

N6-phenylisopropyladenosine

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Authors and Affiliations

  1. Pharmakologisches Institut der Universität Heidelberg, Im Neuenheimer Feld 366, D-6900, Heidelberg, Federal Republic of Germany

    Martin J. Lohse, Sabine Böser, Karl-Norbert Klotz & Ulrich Schwabe

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  1. Martin J. Lohse
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  2. Sabine Böser
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  3. Karl-Norbert Klotz
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  4. Ulrich Schwabe
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Lohse, M.J., Böser, S., Klotz, KN. et al. Affinities of barbiturates for the GABA-receptor complex and A1 adenosine receptors: a possible explanation of their excitatory effects. Naunyn-Schmiedeberg's Arch Pharmacol 336, 211–217 (1987). https://doi.org/10.1007/BF00165807

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  • DOI: https://doi.org/10.1007/BF00165807

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