title: Probing distal regions of the A2B adenosine receptor by quantitative structure-activity relationship modeling of known and novel agonists.
abstract: The binding modes at the A 2B adenosine receptor (AR) of 72 derivatives of adenosine and its 5'- N-methyluronamide with diverse substitutions at the 2 and N (6) positions were studied using a molecular modeling approach. The compounds in their receptor-docked conformations were used to build CoMFA and CoMSIA quantitative structure-activity relationship models. Various parameters, including different types of atomic charges, were examined. The best statistical parameters were obtained with a joint CoMFA and CoMSIA model: R (2) = 0.960, Q (2) = 0.676, SEE = 0.175, F = 158, and R (2) test = 0.782 for an independent test set containing 18 compounds. On the basis of the modeling results, four novel adenosine analogues, having elongated or bulky substitutions at N (6) position and/or 2 position, were synthesized and evaluated biologically. All of the proposed compounds were potent, full agonists at the A 2B AR in adenylate cyclase studies. Thus, in support of the modeling, bulky substitutions at both positions did not prevent A 2B AR activation, which predicts separate regions for docking of these moieties.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Ivanov
authors.forename: Ben
authors.initials: B
authors.lastname: Wang
authors.forename: Athena M
authors.initials: AM
authors.lastname: Klutz
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Chen
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D058908:Adenosine A2 Receptor Agonists; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D043704:Receptor, Adenosine A2B / Q000737:chemistry; D055672:Static Electricity; D013237:Stereoisomerism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D043704:Receptor, Adenosine A2B; D000241:Adenosine