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Derivatives of Benzimidazol‐2‐ylquinoline and Benzimidazol‐2‐ylisoquinoline as Selective A 1 Adenosine Receptor Antagonists with Stimulant Activity on Human Colon Motility
Author(s) -
Cosimelli Barbara,
Taliani Sabrina,
Greco Giovanni,
Novellino Ettore,
Sala Annalisa,
Severi Elda,
Da Settimo Federico,
La Motta Concettina,
Pugliesi Isabella,
Antonioli Luca,
Fornai Matteo,
Colucci Rocchina,
Blandizzi Corrado,
Daniele Simona,
Trincavelli Maria Letizia,
Martini Claudia
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100284
Subject(s) - isoquinoline , chemistry , stereochemistry , antagonist , adenosine receptor , quinoxaline , adenosine , receptor , potency , pharmacology , in vitro , biochemistry , biology , agonist , organic chemistry
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)‐1 H ‐benzimidazol‐2‐yl]isoquinoline 4 b exhibited the best combination of potency toward the A 1 AR ( K i =1.4 n M ) and selectivity against the A 2A ( K i >10 μ m), A 2B ( K i >10 μ m) , and A 3 ARs ( K i >1 μ M ). Functional experiments in circular smooth muscle preparations of isolated human colon showed that 4 b 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 4 b is a suitable starting point for the development of novel agents endowed with stimulant properties on colonic activity.