Synthesis and biological evaluation of novel N6-[4-(substituted)sulfonamidophenylcarbamoyl]adenosine-5'-uronamides as A3 adenosine receptor agonists.
A new series of 1-deoxy-1-[(6-(4-(substituted-aminosulfonyl)phenyl)amino)carbonylamino-9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamides (83-102) have been synthesized and tested at the human A3 adenosine receptor subtype. All the derivatives described in this work displayed affinity versus this receptor in the nanomolar range and good selectivity versus A1 adenosine receptor subtype, confirming that the p-sulfonamido moiety positively affected the activity of the molecules. The best substituents at the sulfonamido nucleus were found to be small alkyl groups, like methyl, isopropyl, ethyl, or allyl moieties (compounds 96-100), whereas monosubstitution at the amino group led to a decrease in A3 affinity values. The selectivity versus A1 adenosine receptor subtype is increased when the amino group in the sulfonamido core is represented by a hydrogenated heterocyclic ring like piperidine, morpholine, or pyrroline. Bulky groups, like adamantane and alkyl chains with more than four carbon atoms, are detrimental for the affinity and the selectivity of the A3 adenosine receptor agonists described here.
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy. pgb@dns.unife.it
Pier Giovanni
PG
Baraldi
Francesca
F
Fruttarolo
Mojgan Aghazadeh
MA
Tabrizi
Romeo
R
Romagnoli
Delia
D
Preti
Andrea
A
Bovero
Maria Josè
MJ
Pineda de Las Infantas
Allan
A
Moorman
Katia
K
Varani
Pier Andrea
PA
Borea
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008024:Ligands; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014574:Uronic Acids / Q000737:chemistry*
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D000577:Amides; D008024:Ligands; D013449:Sulfonamides; D014574:Uronic Acids; D000242:Cyclic AMP; D000241:Adenosine