title: Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists.
abstract: On the basis of potent and selective A(3) adenosine receptor (AR) antagonist, 2-chloro-N(6)-(3-iodobenzyl)-4'-thioadenosine-5'-N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5'-N,N-dialkyluronamide derivatives, synthesized from D-gulonic gamma-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5'-uronamide was essential for the pure A(3)AR antagonism. 5'-N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5'-N,N-dialkyl or 5'-N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A(3)AR. A N(6)-(3-bromobenzyl) derivative 6c (K(i)=9.32 nM) exhibited the highest binding affinity at the human A(3)AR with very low binding affinities to other AR subtypes.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea. lakjeong@ewha.ac.kr
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Shantanu
authors.initials: S
authors.lastname: Pal
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Choi
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Amit R
authors.initials: AR
authors.lastname: Patel
authors.forename: Wanda
authors.initials: W
authors.lastname: Williams
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Hee-Doo
authors.initials: HD
authors.lastname: Kim
mesh_terms: D058918:Adenosine A3 Receptor Antagonists; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014574:Uronic Acids / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D000577:Amides; D014574:Uronic Acids