Synthesis and biological evaluation of 2-amino-3-(4-chlorobenzoyl)-4-[(4-arylpiperazin-1-yl)methyl]-5-substituted-thiophenes. effect of the 5-modification on allosteric enhancer activity at the A1 adenosine receptor.
We have recently reported a detailed structure-activity relationship study around a wide series of 2-amino-3-(4-chlorobenzoyl)-4-[(4-arylpiperazin-1-yl)methyl]thiophene derivatives as potent allosteric enhancers of the A(1) adenosine receptor. In the current study, we have continued to explore the potential of these molecules by synthesizing of a novel series of analogues that share a common 2-amino-3-(4-chlorobenzoyl)thiophene nucleus. Modifications were focused on varying the nature and the position of electron-withdrawing or electron-releasing groups on the phenyl of an arylpiperazine moiety attached at the 4-position of the thiophene ring by a methylene chain, combined with the presence of small alkyl groups (methyl or ethyl), bromine, or aryl moieties at the thiophene C-5 position. In this series of compounds, substitution at the 5-position had a fundamental effect on activity, with the 5-aryl group contributing additively to the allosteric enhancer activity. The thiophene C-5 aryl derivatives 4ad, 4ak, and 4al were the most active compounds in binding and functional experiments.
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy. rmr@unife.it
Romeo
R
Romagnoli
Pier Giovanni
PG
Baraldi
Maria Dora
MD
Carrion
Carlota Lopez
CL
Cara
Olga
O
Cruz-Lopez
Maria Kimatrai
MK
Salvador
Delia
D
Preti
Mojgan Aghazadeh
MA
Tabrizi
Allan R
AR
Moorman
Fabrizio
F
Vincenzi
Pier Andrea
PA
Borea
Katia
K
Varani
D000494:Allosteric Regulation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D043682:Receptor, Adenosine A1 / Q000187:drug effects* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
D043682:Receptor, Adenosine A1; D013876:Thiophenes