The thermodn. parameters ΔGθ, ΔHθ, and ΔSθ of the binding equil. of 12 adenosine agonists and 11 xanthine antagonists of A1 adenosine receptors in rat brain (minus striatum) membranes were detd. by means of affinity measurements carried out at different temps. (0, 10, 20, 25, 30, and 35 °) and van't Hoff plots. Affinity consts. were obtained from satn. expts. for [3H]-N6-cyclohexyladenosine ([3H]-CHA) or inhibition assays for all other compds. by the use of [3H]-CHA as specific A1 radioligand. Scatchard plots were monophasic at all temps. investigated, indicating the presence of only one class of high-affinity binding sites. All van't Hoff plots were strictly linear in the range 0-25° (which was used for interpolation) and had pos. slopes for antagonists and neg. slopes for agonists. The av. receptor d., Bmax, was essentially temp.-independent and const. for all ligands, resulting in an av. value of 187 fmol/mg of protein. The ΔHθ and ΔSθ values fell in the ranges 18.7 ≤ ΔHθ ≤ 46.0 kJ/mol and 203.9 ≤ ΔSθ ≤ 355.5 J/°K/mol for agonists, and -36.6 ≤ ΔHθ ≤ -12.3 kJ/mol and -21.6 ≤ ΔSθ ≤ 60.1 J/°K/mol for antagonists, showing that agonist binding was entropy-driven while that of antagonists was mainly enthalpy-driven. The differences in thermodn. behavior of agonists and antagonists were interpreted in terms of a simplified general model of drug-receptor interaction. A specific functional model of the A1 receptor binding site was suggested, which accounts for the role played by the ribose moiety of adenosine drugs in detg. both affinity and intrinsic activity of agonists. The intercorrelation between ΔHθ and ΔSθ values is briefly discussed in terms of the enthalpy-entropy compensation rule.

Binding thermodynamics of A1 adenosine receptor ligands

BOREA, Pier Andrea;VARANI, Katia;GUERRA, Laura;GILLI, Paola;GILLI, Gastone
1992

Abstract

The thermodn. parameters ΔGθ, ΔHθ, and ΔSθ of the binding equil. of 12 adenosine agonists and 11 xanthine antagonists of A1 adenosine receptors in rat brain (minus striatum) membranes were detd. by means of affinity measurements carried out at different temps. (0, 10, 20, 25, 30, and 35 °) and van't Hoff plots. Affinity consts. were obtained from satn. expts. for [3H]-N6-cyclohexyladenosine ([3H]-CHA) or inhibition assays for all other compds. by the use of [3H]-CHA as specific A1 radioligand. Scatchard plots were monophasic at all temps. investigated, indicating the presence of only one class of high-affinity binding sites. All van't Hoff plots were strictly linear in the range 0-25° (which was used for interpolation) and had pos. slopes for antagonists and neg. slopes for agonists. The av. receptor d., Bmax, was essentially temp.-independent and const. for all ligands, resulting in an av. value of 187 fmol/mg of protein. The ΔHθ and ΔSθ values fell in the ranges 18.7 ≤ ΔHθ ≤ 46.0 kJ/mol and 203.9 ≤ ΔSθ ≤ 355.5 J/°K/mol for agonists, and -36.6 ≤ ΔHθ ≤ -12.3 kJ/mol and -21.6 ≤ ΔSθ ≤ 60.1 J/°K/mol for antagonists, showing that agonist binding was entropy-driven while that of antagonists was mainly enthalpy-driven. The differences in thermodn. behavior of agonists and antagonists were interpreted in terms of a simplified general model of drug-receptor interaction. A specific functional model of the A1 receptor binding site was suggested, which accounts for the role played by the ribose moiety of adenosine drugs in detg. both affinity and intrinsic activity of agonists. The intercorrelation between ΔHθ and ΔSθ values is briefly discussed in terms of the enthalpy-entropy compensation rule.
Borea, Pier Andrea; Varani, Katia; Guerra, Laura; Gilli, Paola; Gilli, Gastone
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/461744
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