Structure-activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists.
On the basis of potent and selective binding affinity of truncated 4'-thioadenosine derivatives at the human A(3) adenosine receptor (AR), their bioisosteric 4'-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-D-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N(6) positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A(3) AR. They were less potent than the corresponding 4'-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X=Cl, R=3-bromobenzyl) showed the highest binding affinity (K(i)=13.0+/-6.9 nM) at the hA(3) AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4'-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA(3) AR-expressing CHO cells. Although the 4'-oxo series were less potent than the 4'-thio series, this class of human A(3) AR antagonists is also regarded as another good template for the design of A(3) AR antagonists and for further drug development.
Pal
Shantanu
S
Department of Bioinspired Science and Division of Life and Pharmaceutical Sciences, Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Choi
Won Jun
WJ
Choe
Seung Ah
SA
Heller
Cara L
CL
Gao
Zhan-Guo
ZG
Chinn
Moshe
M
Jacobson
Kenneth A
KA
Hou
Xiyan
X
Lee
Sang Kook
SK
Kim
Hea Ok
HO
Jeong
Lak Shin
LS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000262:Adenylyl Cyclases / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D005576:Colforsin / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C541664:(2R,3R,4R)-2-(2-chloro-6-(3-bromobenzylamino)-9H-purin-9-yl)-tetrahydrofuran-3,4-diol; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D005663:Furans; D011687:Purines; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D043683:Receptors, Adenosine A2; D013872:Thionucleosides; D005576:Colforsin; C050070:4'-thioadenosine; D000262:Adenylyl Cyclases; D000241:Adenosine