N(6)-[(hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5'-N-ethylcarboxamido-adenosines: the first example of adenosine-related structures with potent agonist activity at the human A(2B) adenosine receptor.
A new series of N(6)-[(hetero)aryl/(cyclo)alkyl-carbamoyl-methoxy-phenyl]-(2-chloro)-5'-N-ethylcarboxamido-adenosines (24-43) has been synthesised and tested in binding assays at hA(1), hA(2A) and hA(3) adenosine receptors, and in a functional assay at the hA(2B) subtype. The examined compounds displayed high potency in activating A(2B) receptors with good selectivity versus A(2A) subtypes. The introduction of an unsubstituted 4-[(phenylcarbamoyl)-methoxy]-phenyl chain at the N(6) position of 5'-N-ethylcarboxamido-adenosine led us to the recognition of compound 24 as a full agonist displaying the highest efficacy of the series (EC(50) hA(2B)=7.3 nM). These compounds represent the first report about adenosine-related structures capable of activating hA(2B) subtype in the low nanomolar range.
Baraldi
Pier Giovanni
PG
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy. pgb@ifeuniv.unife.it
Preti
Delia
D
Tabrizi
Mojgan Aghazadeh
MA
Fruttarolo
Francesca
F
Saponaro
Giulia
G
Baraldi
Stefania
S
Romagnoli
Romeo
R
Moorman
Allan R
AR
Gessi
Stefania
S
Varani
Katia
K
Borea
Pier Andrea
PA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D016466:CHO Cells; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D011869:Radioligand Assay
D058908:Adenosine A2 Receptor Agonists; D002219:Carbamates; D007202:Indicators and Reagents; D000242:Cyclic AMP; D000241:Adenosine