title: Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety.
abstract: We have found previously that structural features of adenosine derivatives, particularly at the N6- and 2-positions of adenine, determine the intrinsic efficacy as A3 adenosine receptor (AR) agonists. Here, we have probed this phenomenon with respect to the ribose moiety using a series of ribose-modified adenosine derivatives, examining binding affinity and activation of the human A3 AR expressed in CHO cells. Both 2'- and 3'-hydroxyl groups in the ribose moiety contribute to A3 AR binding and activation, with 2'-OH being more essential. Thus, the 2'-fluoro substitution eliminated both binding and activation, while a 3'-fluoro substitution led to only a partial reduction of potency and efficacy at the A3 AR. A 5'-uronamide group, known to restore full efficacy in other derivatives, failed to fully overcome the diminished efficacy of 3'-fluoro derivatives. The 4'-thio substitution, which generally enhanced A3 AR potency and selectivity, resulted in 5'-CH2OH analogues (10 and 12) which were partial agonists of the A3 AR. Interestingly, the shifting of the N6-(3-iodobenzyl)adenine moiety from the 1'- to 4'-position had a minor influence on A3 AR selectivity, but transformed 15 into a potent antagonist (16) (Ki = 4.3 nM). Compound 16 antagonized human A3 AR agonist-induced inhibition of cyclic AMP with a K(B) value of 3.0 nM. A novel apio analogue (20) of neplanocin A, was a full A3 AR agonist. The affinities of selected, novel analogues at rat ARs were examined, revealing species differences. In summary, critical structural determinants for human A3 AR activation have been identified, which should prove useful for further understanding the mechanism of receptor activation and development of more potent and selective full agonists, partial agonists and antagonists for A3 ARs.
authors.affiliation: Laboratory of Bioorganic Chemistry, Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Choi
authors.forename: Dae Hong
authors.initials: DH
authors.lastname: Shin
authors.forename: Eleonora
authors.initials: E
authors.lastname: Elhalem
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Comin
authors.forename: Neli
authors.initials: N
authors.lastname: Melman
authors.forename: Liaman
authors.initials: L
authors.lastname: Mamedova
authors.forename: Ariel S
authors.initials: AS
authors.lastname: Gross
authors.forename: Juan B
authors.initials: JB
authors.lastname: Rodriguez
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D051381:Rats; D043684:Receptor, Adenosine A3 / Q000187:drug effects / Q000378:metabolism*; D012266:Ribose / Q000737:chemistry*; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D043684:Receptor, Adenosine A3; D012266:Ribose; D000241:Adenosine