Thermodynamics of γ-aminobutyric acid type A receptor binding differentiate agonists from antagonists

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Specific binding of the γ-aminobutyric acid (GABA)(A) antagonist [3H]SR 95531 to synaptosomal membranes of rat whole brain was examined between 0° and 37°. Scatchard analysis revealed two (high and low affinity) populations of [3H]SR 95531 binding sites. The K(d) values increased with increasing temperature. K(i) values for GABA(A) agonists and antagonists were determined from the displacement of [3H]SR 95531 binding at a low concentration (1.8 nM) of [3H]SR 95531, which binds predominantly to high affinity sites. For most compounds van't Hoff plots (-In K(i), i.e., In K(a), versus 1/T) were linear between 0° and 37°. Curvilinear van't Hoff plots for the antagonists R 5135 and bicuculline methiodide can be attributed to their hydrophobic binding interactions. The enthalpy changes of binding (ΔH°) were positive for the agonists (muscimol, isoguvacine, GABA, 4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridin-3-ol hydrochloride, and imidazole-4-acetic acid) and negative for the antagonists (pitrazepin, bicuculline methiodide, R 5135, SR 95531, and SR 95103). Separation of the enthalpic and entropic components of the Gibbs free energy changes of binding (ΔG°) revealed that binding of the antagonists is driven by both the enthalpic and entropic terms, whereas that of the agonists is driven entirely by entropy changes. A plot of the entropic term (-TΔS°) versus the enthalpic term (ΔH°) showed separate patterns for GABA(A) agonists and antagonists, with the partial agonists [5-(4-piperidyl)isoxazol-3-ol, imidazole-4-acetic acid, and 4,5,6,7- tetrahydroisoxazolo[4,5-c]pyridin-3-ol hydrochloride] between them. It is proposed that the entropic term is partly determined by a transition from antagonist to agonist conformation of the GABA(A) binding sites.

Original languageEnglish
Pages (from-to)386-390
Number of pages5
JournalMolecular pharmacology
Issue number2
Publication statusPublished - Aug 1 1994


ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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