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Structure–activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists
- Source :
- Bioorganic & Medicinal Chemistry. 17:3733-3738
- Publication Year :
- 2009
- Publisher :
- Elsevier BV, 2009.
-
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.
- Subjects :
- Agonist
Adenosine
medicine.drug_class
Stereochemistry
Clinical Biochemistry
Adenosine A3 Receptor Antagonists
Pharmaceutical Science
Thio
CHO Cells
Adenosine A1 Receptor Antagonists
Biochemistry
Chemical synthesis
Cyclase
Article
Cell Line
Structure-Activity Relationship
Cricetulus
Cricetinae
Drug Discovery
medicine
Animals
Humans
Structure–activity relationship
Furans
Molecular Biology
Thionucleosides
Receptor, Adenosine A1
Receptors, Adenosine A2
Chemistry
Colforsin
Receptor, Adenosine A3
Organic Chemistry
Adenosine receptor
Adenosine A2 Receptor Antagonists
Purines
Molecular Medicine
Adenylyl Cyclases
medicine.drug
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....43aa025aaa29d4deef99c4ea7de9c6ca