title: Derivatives of benzimidazol-2-ylquinoline and benzimidazol-2-ylisoquinoline as selective A1 adenosine receptor antagonists with stimulant activity on human colon motility.
abstract: A number of quinolines and isoquinolines connected in various ways to a substituted benzimidazol-2-yl system were synthesized and evaluated as novel antagonists of adenosine receptors (ARs) by competition experiments using human A(1), A(2A), and A(3) ARs. The new compounds were designed based on derivatives of 2-(benzimidazol-2-yl)quinoxaline, previously reported as potent and selective antagonists of A(1) and A(3) ARs. Among these, 3-[4-(ethylthio)-1H-benzimidazol-2-yl]isoquinoline 4b exhibited the best combination of potency toward the A(1) AR (K(i) =1.4 nM) and selectivity against the A(2A) (K(i) >10 μM), A(2B) (K(i)>10 μM), and A(3) ARs (K(i)>1 μM). Functional experiments in circular smooth muscle preparations of isolated human colon showed that 4b behaves as a potent and selective antagonist of the A(1) AR in the neuromuscular compartment of this intestinal region. Biological and pharmacological data suggest that 4b is a suitable starting point for the development of novel agents endowed with stimulant properties on colonic activity.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy. barbara.cosimelli@unina.it
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Annalisa
authors.initials: A
authors.lastname: Sala
authors.forename: Elda
authors.initials: E
authors.lastname: Severi
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Isabella
authors.initials: I
authors.lastname: Pugliesi
authors.forename: Luca
authors.initials: L
authors.lastname: Antonioli
authors.forename: Matteo
authors.initials: M
authors.lastname: Fornai
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D058916:Adenosine A1 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003106:Colon / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism
chemical_list: C569483:3-(4-(ethylthio)-1H-benzimidazol-2-yl)isoquinoline; D000199:Actins; D058916:Adenosine A1 Receptor Antagonists; D001562:Benzimidazoles; D007546:Isoquinolines; D011804:Quinolines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; C031000:benzimidazole; C037219:quinoline; C039109:isoquinoline