Thermodynamics of A2B adenosine receptor binding discriminates agonistic from antagonistic behaviour |
| |
Authors: | Gessi Stefania Fogli Eleonora Sacchetto Valeria Varani Katia Merighi Stefania Leung Edward Lennan Stephen Mac Borea Pier Andrea |
| |
Affiliation: | a Department of Clinical and Experimental Medicine, Pharmacology Unit and Interdisciplinary Center for the Study of Inflammation, Ferrara, Italy b King Pharmaceutical, Inc., Research and Development, Cary, NC, United States |
| |
Abstract: | Thermodynamic parameters ΔG°, ΔH° and ΔS° of the binding equilibrium of 12 ligands (six agonists and six antagonists) to the A2B adenosine receptor subtype have been determined by affinity measurements carried out on HEK 293 cells stably transfected with human A2B adenosine receptors at six different temperatures (4, 10, 15, 20, 25, 30 °C) and van’t Hoff plot analysis have been performed. Affinity constants were obtained from saturation experiments of [3H]MRE 2029-F20 or by its displacement in inhibition assays for the other compounds. van’t Hoff plots were essentially linear in the temperature range investigated, showing that the ΔCp° of the binding equilibrium is nearly zero. Thermodynamic parameters are in the range 7 ≤ ΔH° ≤ 23 kJ mol−1and 123 ≤ ΔS° ≤ 219 J K−1 mol−1 for agonists and −40 ≤ ΔH° ≤ −20 kJ mol−1 and 10 ≤ ΔS° ≤ 91 J K−1 mol−1 for antagonists indicating that agonistic binding is always totally entropy-driven while antagonistic binding is enthalpy and entropy-driven. In the −TΔS° versus ΔH° plot the thermodynamic data are clearly arranged in separate clusters for agonists and antagonists, which, therefore, turn out to be thermodynamically discriminated. |
| |
Keywords: | AB-MECA, 4-aminobenzyl-5&prime -N-methylcarboxamidoadenosine CGS 21680, 2-[p-(carboxyethyl)-phenethylamino]-NECA CGS 15943, 5-amino-9-chloro-2-(furyl)1,2,4-triazolo[1,5-c]quinazoline CHA, N6-cyclohexyladenosine Cl-IB-MECA, N6(3-iodobenzyl)2-chloroadenosine-5&prime N-methyluronamide Compound 24, 1-deoxy-1-[6-{4-[(phenylcarbamoyl)-methoxy]phenylamino}-9H-purin-9-yl]-N-ethyl-β- smallcaps" >d-ribofuranuronamide Compound 34, 1-deoxy-1-[6-{4-[(4-tert-butyl-phenylcarbamoyl)-methoxyl-phenylamino}-9H-purin-9-yl]-N-ethyl-β- smallcaps" >d-ribofuranuronamide Compound 17b, N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenyl-acetamide Compound 21b, 2-(4-benzyloxy-phenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8yl)-1-methyl-1H-pyrazol-3-yl]-acetamide CPA, N6-cyclopentyladenosine CPT, 8-cyclopentylxanthine DPCPX, 1,3-dipropyl-8-cyclopentyl-xanthine DPSPX, 1,3-dipropyl-8-sulfophenyl-xanthine hHEK293-A2B, HEK293 cells transfected with human A2B adenosine receptor IB-MECA, N6-(3-iodobenzyl) adenosine-5&prime -N-methyluronamide IBMX, 3-isobutyl-1-methylxanthine MRE 2029-F20, N-benzo[1,3]dioxol-5-yl-2-[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl-oxy]-acetamide] MRE 3008-F20, 5-N-(4-methoxyphenylcarbamoyl)-amino-8-propyl-2-(2-furyl)-pyrazolo[4,3e]-1,2,4triazolo[1,5c]pyrimidine MRE 3020-F20, 5-N-(3-chlorophenylcarbamoyl)-amino-8-ethyl-2(2-furyl)pyrazolo[4,3e]1,2,4triazolo[1,5c]pyrimidine MRE 3005-F20, 5-N-(4-methoxyphenylcarbamoyl)amino-8-phenyl-ethyl-2-(2-furyl)-pyrazolo-[4,3e]1,2,4-triazolo[1,5c]-pyrimidine NECA, 5&prime -N-ethyl-carboxamidoadenosine 8-PT, 8-phenyltheophylline R-PIA, R(&minus )-N6-(2-phenyl-isopropyl)adenosine SCH 58261, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]-pyrimidine SCH 63390, 5-amino-7-(3-phenylpropyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine S-PIA, S(&minus )N6-(2-phenyl-isopropyl)adenosine ZM, 241385 (4-(2-[7-amino-2-(2-furyl)-[1,2,4]triazolo-[2,32][1,3,6]triazinyl-amino]ethyl)-phenol) |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|