title: Development of Polar Adenosine A2A Receptor Agonists for Inflammatory Bowel Disease: Synergism with A2B Antagonists.
abstract: Adenosine A2A receptor agonists for the local treatment of inflammatory bowel disease (IBS) were designed and synthesized. Polar groups were introduced to prevent peroral absorption and subsequent systemic, e.g., hypotensive, side effects. 4-(2-{6-Amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-2-ylthio}ethyl)benzenesulfonic acid (7, PSB-0777) was selected for further evaluation in rat ileum/jejunum preparations in ex vivo experiments. Compound 7 significantly improved impaired acetylcholine-induced contractions induced by 2,4,6-trinitrobenzenesulfonic acid and showed synergism with an A2B-selective antagonist. Thus, nonabsorbable, locally active A2A agonists, as a monotherapy or in combination with an A2B antagonist, may be an efficient novel treatment for IBS, preventing the severe systemic side effects of known A2A agonists.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: El-Tayeb
authors.affiliation: University of Leipzig , Institute of Pharmacy, Talstrasse 33, D-04109 Leipzig, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Michael
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Aliaa
authors.initials: A
authors.lastname: Abdelrahman
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Behrenswerth
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Gollos
authors.affiliation: University of Leipzig , Institute of Pharmacy, Talstrasse 33, D-04109 Leipzig, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Nieber
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
keywords: A2A receptor agonist; A2B receptor antagonist; anti-inflammatory drug; inflammatory bowel disease; nonabsorbable A2A receptor agonist