Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5'-ribofuran-uronamide moiety.
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.
Gao
Zhan-Guo
ZG
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Joshi
Bhalchandra V
BV
Klutz
Athena M
AM
Kim
Soo-Kyung
SK
Lee
Hyuk Woo
HW
Kim
Hea Ok
HO
Jeong
Lak Shin
LS
Jacobson
Kenneth A
KA
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
D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000577:Amides; D005663:Furans; D043684:Receptor, Adenosine A3; D012266:Ribose; D000241:Adenosine; C039281:furan