title: Extended N(6) substitution of rigid C2-arylethynyl nucleosides for exploring the role of extracellular loops in ligand recognition at the A3 adenosine receptor.
abstract: 2-Arylethynyl-(N)-methanocarba adenosine 5'-methyluronamides containing rigid N(6)-(trans-2-phenylcyclopropyl) and 2-phenylethynyl groups were synthesized as agonists for probing structural features of the A3 adenosine receptor (AR). Radioligand binding confirmed A3AR selectivity and N(6)-1S,2R stereoselectivity for one diastereomeric pair. The environment of receptor-bound, conformationally constrained N(6) groups was explored by docking to an A3AR homology model, indicating specific hydrophobic interactions with the second extracellular loop able to modulate the affinity profile. 2-Pyridylethynyl derivative 18 was administered orally in mice to reduce chronic neuropathic pain in the chronic constriction injury model.
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
authors: Dilip K
authors: DK
authors: Tosh
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
authors: Silvia
authors: S
authors: Paoletta
authors: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors: Zhoumou
authors: Z
authors: Chen
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
authors: Steven M
authors: SM
authors: Moss
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
authors: Zhan-Guo
authors: ZG
authors: Gao
authors: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors: Daniela
authors: D
authors: Salvemini
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA. Electronic address: kajacobs@helix.nih.gov.
authors: Kenneth A
authors: KA
authors: Jacobson
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D059350:Chronic Pain / Q000188:drug therapy; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D009705:Nucleosides; D043684:Receptor, Adenosine A3
keywords: Adenylate cyclase; G protein-coupled receptor; Molecular modeling; Purines; Radioligand binding; Structure activity relationship