期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 151, 期 -, 页码 199-213出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.03.067
关键词
Adenosine; Adenosine receptors; Adenosine receptor antagonists; A(1) adenosine receptor; Purinergic receptors; Mouse ileum
资金
- University of Camerino (Fondo di Ricerca di Ateneo and Progetto) [FAR FPI000042]
- Ministry of Research (PRIN) [2015E8EMCM_008]
The synthesis of 9-alkyl substituted adenine derivatives presenting aromatic groups and cycloalkyl rings in 8- and N-6-position, respectively, is reported. The compounds were tested with radioligand binding studies showing, in some cases, a low nanomolar A(1) adenosine receptor affinity and a very good selectivity versus the other adenosine receptor subtypes. Functional assays at human adenosine receptors and at a mouse ileum tissue preparation clearly demonstrate the antagonist profile of these molecules, with inhibitory potency at nanomolar level. A molecular modeling study, consisting in docking analysis at the recently reported A(1) adenosine receptor crystal structure, was performed for the interpretation of the obtained pharmacological results. The N-6-cyclopentyl-9-methyl-8-phenyladenine (17), resulting the most active derivative of the series (K-i = 2.8 nM and IC50 = 14 nM), was also very efficacious in counteracting the effect of the agonist CCPA on mouse ileum contractility. This new compound represents a tool for the development of new agents for the treatment of intestinal diseases as constipation and postoperative ileus. (C) 2018 Elsevier Masson SAS. All rights reserved.
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