Discovery of a new nucleoside template for human A3 adenosine receptor ligands: D-4'-thioadenosine derivatives without 4'-hydroxymethyl group as highly potent and selective antagonists.
Truncated D-4'-thioadenosine derivatives lacking the 4'-hydroxymethylene moiety were synthesized starting from D-mannose, using cyclization to the 4-thiosugar and one-step conversion of the diol to the acetate as key steps. At the human A3 adenosine receptor (AR), N6-substituted purine analogues bound potently and selectively and acted as antagonists in a cyclic AMP functional assay. An N6-(3-chlorobenzyl)purine analogue 9b displayed a Ki value of 1.66 nM at the human A3 AR. Thus, truncated D-4'-thioadenosine is an excellent template for the design of novel A3 AR antagonists to act at both human and murine species.
Jeong
Lak Shin
LS
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea. lakjeong@ewha.ac.kr
Choe
Seung Ah
SA
Gunaga
Prashantha
P
Kim
Hea Ok
HO
Lee
Hyuk Woo
HW
Lee
Sang Kook
SK
Tosh
Dilip K
DK
Patel
Amit
A
Palaniappan
Krishnan K
KK
Gao
Zhan-Guo
ZG
Jacobson
Kenneth A
KA
Moon
Hyung Ryong
HR
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D013872:Thionucleosides / Q000737:chemistry / Q000494:pharmacology*
D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D043684:Receptor, Adenosine A3; D013872:Thionucleosides; C050070:4'-thioadenosine; D000241:Adenosine