title: Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5'-ribofuran-uronamide moiety.
abstract: The highly selective agonists of the A(3) adenosine receptor (AR), Cl-IB-MECA (2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine), and its 4'-thio analogue, were successfully converted into selective antagonists simply by appending a second N-methyl group on the 5'-uronamide position. The 2-chloro-5'-(N,N-dimethyl)uronamido analogues bound to, but did not activate, the human A(3)AR, with K(i) values of 29 nM (4'-O) and 15 nM (4'-S), showing >100-fold selectivity over A(1), A(2A), and A(2B)ARs. Competitive antagonism was demonstrated by Schild analysis. The 2-(dimethylamino)-5'-(N,N-dimethyl)uronamido substitution also retained A(3)AR selectivity but lowered affinity.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Bhalchandra V
authors.initials: BV
authors.lastname: Joshi
authors.forename: Athena M
authors.initials: AM
authors.lastname: Klutz
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000494:pharmacology*; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000577:Amides / Q000737:chemistry*; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D005663:Furans / Q000737:chemistry*; D006801:Humans; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D012266:Ribose / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000577:Amides; D005663:Furans; D043684:Receptor, Adenosine A3; D012266:Ribose; D000241:Adenosine; C039281:furan