Structure-activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists.

Abstract:

: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.

journal_name

Bioorg Med Chem

authors

Pal S,Choi WJ,Choe SA,Heller CL,Gao ZG,Chinn M,Jacobson KA,Hou X,Lee SK,Kim HO,Jeong LS

doi

10.1016/j.bmc.2009.03.034

subject

Has Abstract

pub_date

2009-05-15 00:00:00

pages

3733-8

issue

10

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(09)00288-0

journal_volume

17

pub_type

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