Temperature and anion dependence of allosteric interactions at the gamma-aminobutyric acid-benzodiazepine receptor.
The temperature dependence of [3H]flunitrazepam ([3H]FNZ) binding to rat brain membranes was examined in the presence of the anaesthetics, pentobarbitone, alphaxalone and propofol. Van't Hoff plots showed the binding of FNZ to be largely enthalpy driven. Alphaxalone and propofol increased the entropy of the binding reaction but not the enthalpy and therefore did not show temperature dependence in their efficacy. In contrast, pentobarbitone increased the enthalpy of FNZ binding and, therefore, is more efficacious at low temperatures. The EC50 values of all three modulators increased with temperature indicating that their interactions with the receptor may be enthalpy driven. The EC50 values of all three modulators were also anion dependent, showing a decrease in the presence of gamma-aminobutyric acid (GABAA)-channel permeant anions. The efficacies of alphaxalone and pentobarbitone, but not that of propofol, also increased with increasing chloride ion concentration. The results indicate that all three modulators interact with the GABAA receptor at distinct recognition sites.
Prince
R J
RJ
Department of Pharmacology, School of Pharmacy, University of London, U.K.
Simmonds
M A
MA
D000818:Animals; D000838:Anions; D001667:Binding, Competitive; D001923:Brain Chemistry; D004347:Drug Interactions; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010424:Pentobarbital / Q000494:pharmacology; D011277:Pregnanediones / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013696:Temperature
D000838:Anions; D011277:Pregnanediones; D011963:Receptors, GABA-A; D005445:Flunitrazepam; C006477:alphaxalone; D010424:Pentobarbital; D015742:Propofol