title: 2-Alkynyl derivatives of adenosine and adenosine-5'-N-ethyluronamide as selective agonists at A2 adenosine receptors.
abstract: In the search for more selective A2-receptor agonists and on the basis that appropriate substitution at C2 is known to impart selectivity for A2 receptors, 2-alkynyladenosines 2a-d were resynthesized and evaluated in radioligand binding, adenylate cyclase, and platelet aggregation studies. Binding of [3H]NECA to A2 receptors of rat striatal membranes was inhibited by compounds 2a-d with Ki values ranging from 2.8 to 16.4 nM. 2-Alkynyladenosines also exhibited high-affinity binding at solubilized A2 receptors from human platelet membranes. Competition of 2-alkynyladenosines 2a-d for the antagonist radioligand [3H]DPCPX and for the agonist [3H]CCPA gave Ki values in the nanomolar range, and the compounds showed moderate A2 selectivity. In order to improve this selectivity, the corresponding 2-alkynyl derivatives of adenosine-5'-N-ethyluronamide 8a-d were synthesized and tested. As expected, the 5'-N-ethyluronamide derivatives retained the A2 affinity whereas the A1 affinity was attenuated, resulting in an up to 10-fold increase in A2 selectivity. A similar pattern was observed in adenylate cyclase assays and in platelet aggregation studies. A 30- to 45-fold selectivity for platelet A2 receptors compared to A1 receptors was found for compounds 8a-c in adenylate cyclase studies.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Cristalli
authors.forename: A
authors.initials: A
authors.lastname: Eleuteri
authors.forename: S
authors.initials: S
authors.lastname: Vittori
authors.forename: R
authors.initials: R
authors.lastname: Volpini
authors.forename: M J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: K N
authors.initials: KN
authors.lastname: Klotz
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide); D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000737:chemistry; D001923:Brain Chemistry; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects*
chemical_list: D011983:Receptors, Purinergic; D019830:Adenosine-5'-(N-ethylcarboxamide); D000262:Adenylyl Cyclases; D000241:Adenosine