Affinities of barbiturates for the GABA-receptor complex and A1 adenosine receptors: a possible explanation of their excitatory effects.
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.
Lohse
M J
MJ
Pharmakologisches Institut der Universität Heidelberg, Federal Republic of Germany.
Böser
S
S
Klotz
K N
KN
Schwabe
U
U
D000818:Animals; D001463:Barbiturates / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003975:Diazepam / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008723:Methohexital / Q000494:pharmacology; D010660:Phenylisopropyladenosine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000502:physiology; D011983:Receptors, Purinergic / Q000378:metabolism* / Q000502:physiology
D001463:Barbiturates; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011963:Receptors, GABA-A; D011983:Receptors, Purinergic; D010660:Phenylisopropyladenosine; C037476:tert-butylbicyclophosphorothionate; D008723:Methohexital; D003975:Diazepam