title: N6-methoxy-2-alkynyladenosine derivatives as highly potent and selective ligands at the human A3 adenosine receptor.
abstract: A new series of N6-methoxy-2-(ar)alkynyladenosine derivatives has been synthesized and tested at the human recombinant adenosine receptors. Binding studies demonstrated that the new compounds possess high affinity and selectivity for the A3 subtype. Among them, compounds bearing an N-methylcarboxamido substituent in the 4'-position showed the highest A3 affinity and selectivity. In particular, the N6-methoxy-2-p-acetylphenylethynylMECA (40; Ki A3 = 2.5 nM, A3 selectivity versus A1 = 21 500 and A2A = 4200) results in one of the most potent and selective agonists at the human A3 adenosine receptor reported so far. Furthermore, functional assay, performed with selected new compounds, revealed that the presence of an alkylcarboxamido group in the 4'-position seems to be essential to obtain full agonists at the A3 subtype. Finally, results of molecular docking analysis were in agreement with binding and functional data and could explain the high affinity and potency of the new compounds.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino, 1, 62032 Camerino, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.forename: Sara
authors.initials: S
authors.lastname: Taffi
authors.forename: Sauro
authors.initials: S
authors.lastname: Vittori
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists; D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D011994:Recombinant Proteins / Q000819:agonists; D012243:Rhodopsin / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D058909:Adenosine A3 Receptor Agonists; D000480:Alkynes; D008024:Ligands; C519098:N6-methoxy-2-(4-acetylphenyl)ethynyl-5'-N-methylcarboxamidoadenosine; D011994:Recombinant Proteins; D012243:Rhodopsin; D000242:Cyclic AMP; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide