Synthesis and biological evaluation of novel 2-amino-3-aroyl-4-neopentyl-5-substituted thiophene derivatives as allosteric enhancers of the A1 adenosine receptor

2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a...

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Published in:Bioorganic & medicinal chemistry 2014-01, Vol.22 (1), p.148-166
Main Authors: Romagnoli, Romeo, Baraldi, Pier Giovanni, Carrion, Maria Dora, Cruz-Lopez, Olga, Cara, Carlota Lopez, Saponaro, Giulia, Preti, Delia, Tabrizi, Mojgan Aghazadeh, Baraldi, Stefania, Moorman, Allan R., Vincenzi, Fabrizio, Borea, Pier Andrea, Varani, Katia
Format: Article
Language:English
Subjects:
2-Amino-3-benzoylthiophene
A1 adenosine receptor
Allosteric modulation
Allosteric Regulation
Animals
CHO Cells
Cricetinae
Cricetulus
G protein-coupled receptors
Humans
Receptor, Adenosine A1 - metabolism
Structure-Activity Relationship
Thiophenes - chemical synthesis
Thiophenes - chemistry
Thiophenes - metabolism
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Summary:2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a factor closely related to activity, with the 4-neopentyl (2,2-dimethylpropyl) substitution showing the greatest enhanced activity. A wide series of 2-amino-3-aroyl-4-neopentylthiophene derivatives with general structure 3, characterized by the presence of different substituents (bromine, aryl and heteroaryl) at the 5-position of the thiophene ring, have been identified as potent AEs at the A1AR. With only one exception, all of the synthesized compounds proved to be superior to the reference compound PD 81,723 in a functional assay. Derivatives 3p, 3u, 3am, 3ap and 3ar were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [3H]CCPA binding to the A1 receptor.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.11.043