title: Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A₂A and A₃ adenosine receptor ligands.
abstract: Truncated N(6)-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy, and Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Xiyan
authors.initials: X
authors.lastname: Hou
authors.forename: Mahesh S
authors.initials: MS
authors.lastname: Majik
authors.forename: Kyunglim
authors.initials: K
authors.lastname: Kim
authors.forename: Yuna
authors.initials: Y
authors.lastname: Pyee
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Lee
authors.forename: Varughese
authors.initials: V
authors.lastname: Alexander
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Chung
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Girish
authors.initials: G
authors.lastname: Chandra
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Seul-Gi
authors.initials: SG
authors.lastname: Park
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Choi
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Khai
authors.initials: K
authors.lastname: Phan
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C570915:2-(6-amino-2-(hex-1-enyl)-9H-purine-9-yl)tetrahydrothiophene-3,4-diol; C570914:2-(6-amino-2-(hex-1-ynyl)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol; D058908:Adenosine A2 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D043684:Receptor, Adenosine A3; D043683:Receptors, Adenosine A2; D013876:Thiophenes; D000242:Cyclic AMP; D000241:Adenosine