title: Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists.
abstract: Purine (N)-methanocarba-5'-N-alkyluronamidoriboside A3 adenosine receptor (A3AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A3AR binding site.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciancetta
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors.forename: Eugene
authors.initials: E
authors.lastname: Warnick
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Connor
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gizewski
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Crane
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Auchampach
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D058909:Adenosine A3 Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D002241:Carbohydrates / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry*; D010146:Pain / Q000188:drug therapy*; D011687:Purines / Q000737:chemistry*; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D058909:Adenosine A3 Receptor Agonists; D002241:Carbohydrates; D009705:Nucleosides; D011687:Purines; D043684:Receptor, Adenosine A3