title: Modulation of adenosine receptor affinity and intrinsic efficacy in adenine nucleosides substituted at the 2-position.
abstract: We studied the structural determinants of binding affinity and efficacy of adenosine receptor (AR) agonists. Substituents at the 2-position of adenosine were combined with N(6)-substitutions known to enhance human A(3)AR affinity. Selectivity of binding of the analogues and their functional effects on cAMP production were studied using recombinant human A(1), A(2A), A(2B), and A(3)ARs. Mainly sterically small substituents at the 2-position modulated both the affinity and intrinsic efficacy at all subtypes. The 2-cyano group decreased hA(3)AR affinity and efficacy in the cases of N(6)-(3-iodobenzyl) and N(6)-(trans-2-phenyl-1-cyclopropyl), for which a full A(3)AR agonist was converted into a selective antagonist; the 2-cyano-N(6)-methyl analogue was a full A(3)AR agonist. The combination of N(6)-benzyl and various 2-substitutions (chloro, trifluoromethyl, and cyano) resulted in reduced efficacy at the A(1)AR. The environment surrounding the 2-position within the putative A(3)AR binding site was explored using rhodopsin-based homology modeling and ligand docking.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), DHHS, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810, USA.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Ohno
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Philippe
authors.initials: P
authors.lastname: Van Rompaey
authors.forename: Susanna
authors.initials: S
authors.lastname: Tchilibon
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: Brian A
authors.initials: BA
authors.lastname: Harris
authors.forename: Ariel S
authors.initials: AS
authors.lastname: Gross
authors.forename: Heng T
authors.initials: HT
authors.lastname: Duong
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000819:agonists / Q000031:analogs & derivatives / Q000737:chemistry; D001665:Binding Sites; D003839:Deoxyadenosines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003839:Deoxyadenosines; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins; D000241:Adenosine