Adenosine receptors are divided into 4 subtypes, A1, A2A, A2B and A3, on the basis of their distinct molecular structures, tissue distribution and pharmacological profile. In particular, adenosine A2B receptors are implicated in mast cell activation and asthma, and therefore in inflammatory processes, vasodilatation, regulation of cell growth, intestinal function, and modulation of neurosecretion, and have been classified as low affinity receptors, in consequence of the high adenosine concentrations requested for their activation. The molecular structures of adenosine receptors remain to be determined, but they seem to be characterized by 7 trans-membrane domains (7TM), most probably having a simple a-helix structure, connected by 3 extracellular and 3 intracellular loops. The present paper describes the results of a preliminary docking study of the potent and selective xanthinic antagonist [N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3- dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yloxy]-acetamide to the A2B adenosinic receptor, making use of a calculated model of the 7-chains bundle available from the literature and where the binding pocket inside the transmembrane domains has been localized on the basis of the published site-mutagenesis studies. From the docking simulation the following conclusions can be drawn: the antagonist molecule occupies a receptor region not involved in the binding of the agonists, and it can form a large number of interactions with the macromolecule which easily can account for its great affinity, when compared with the very low affinities of adenosine and other adenosinic agonists towards A2B receptors.
A preliminary docking study of a potent and selective xanthinic antagonist to the adenosine A2B receptor
FERRETTI, Valeria;
2004
Abstract
Adenosine receptors are divided into 4 subtypes, A1, A2A, A2B and A3, on the basis of their distinct molecular structures, tissue distribution and pharmacological profile. In particular, adenosine A2B receptors are implicated in mast cell activation and asthma, and therefore in inflammatory processes, vasodilatation, regulation of cell growth, intestinal function, and modulation of neurosecretion, and have been classified as low affinity receptors, in consequence of the high adenosine concentrations requested for their activation. The molecular structures of adenosine receptors remain to be determined, but they seem to be characterized by 7 trans-membrane domains (7TM), most probably having a simple a-helix structure, connected by 3 extracellular and 3 intracellular loops. The present paper describes the results of a preliminary docking study of the potent and selective xanthinic antagonist [N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3- dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl- 1H-pyrazol-3-yloxy]-acetamide to the A2B adenosinic receptor, making use of a calculated model of the 7-chains bundle available from the literature and where the binding pocket inside the transmembrane domains has been localized on the basis of the published site-mutagenesis studies. From the docking simulation the following conclusions can be drawn: the antagonist molecule occupies a receptor region not involved in the binding of the agonists, and it can form a large number of interactions with the macromolecule which easily can account for its great affinity, when compared with the very low affinities of adenosine and other adenosinic agonists towards A2B receptors.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
