Temperature dependence of the affinity enhancement of selective adenosine A₁ receptor agonism: a thermodynamic analysis

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• 作者：Dalpiaz ; Alessandro ; Pavan ; Barbara ; Ngos ; Franç ; oise Ngo ; Franchetti ; Palmarisa ; IJzerman ; Adriaan P.
• 关键词：Adenosine A₁ receptor ; Adenosine A₁ receptor agonist ; Allosteric ; Modulation ; Temperature dependence ; Binding thermodynamics
• 刊名：European Journal of Pharmacology
• 出版年：2002
• 出版时间：July 19, 2002
• 年：2002
• 卷：448
• 期：2-3
• 页码：123-131
• 全文大小：207 K

文摘

The 2-amino-benzoylthiophene derivatives LUF 5468 [(2-amino-4-ethyl-5-methyl-3-thienyl)[3-(trifluoromethyl)phenyl]methanone] and LUF 5484 [(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone] have been shown to allosterically enhance the adenosine A₁ receptor agonist binding. We report a thermodynamic analysis of the agonist affinity obtained at human adenosine A₁ receptors, in the presence and absence of LUF 5468 and LUF 5484. Moreover, an analysis of the temperature dependence for association and dissociation rates of N⁶-cyclohexyladenosine (CHA) binding was performed in the absence and presence of LUF 5484. Thermodynamic data were obtained by affinity measurements performed at different temperatures followed by van't Hoff analysis. The results indicate that the agonist binding is always totally entropy-driven, and that the modulators contribute to decrease the ΔG°, ΔH° and ΔS° values. It is concluded that the enhancers are able to increase the non-bonded interactions of the binding site with agonists as CHA, N⁶-cyclopentlyladenosine (CPA), 2′-methyl-N⁶-cyclopentyladenosine (MeCPA) and 2-chloro-2′methyl-N⁶-cyclopentyladenosine (MeCCPA).