title: Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-uronamides as highly potent and selective agonists at the human A3 adenosine receptor.
abstract: We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, 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: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Dae Hong
authors.initials: DH
authors.lastname: Shin
authors.forename: Jeong A
authors.initials: JA
authors.lastname: Lee
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Changrui
authors.initials: C
authors.lastname: Lu
authors.forename: Heng T
authors.initials: HT
authors.lastname: Duong
authors.forename: Prashantha
authors.initials: P
authors.lastname: Gunaga
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Dong Zhe
authors.initials: DZ
authors.lastname: Jin
authors.forename: Moon Woo
authors.initials: MW
authors.lastname: Chun
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014574:Uronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D000577:Amides; D014574:Uronic Acids; D000241:Adenosine