title: Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy.
abstract: Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in place of ribose, which adopts a receptor-preferred conformation. N (6)-Small alkyl derivatives were newly optimized for A3AR affinity and the effects of a 1-deaza-adenine modification probed. 1-Deaza-N (6)-ethyl alkyne 20 (MRS7144, K i 1.7 nM) and 1-aza N (6)-propyl alkyne 12 (MRS7154, K i 1.1 nM) were highly efficacious in vivo. Thus, the presence of N1 is not required for nanomolar binding affinity or potent, long-lasting functional activity. Docking of 1-deaza compounds to a receptor homology model confirmed a similar binding mode as previously reported 1-aza derivatives. This is the first demonstration in nonribose adenosine analogues that the 1-deaza modification can maintain high A3AR affinity, selectivity, and efficacy.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892-0810, United States.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892-0810, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Crane
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: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892-0810, United States.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , 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: Elizabeth
authors.initials: E
authors.lastname: Gizewski
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: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892-0810, United States.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
keywords: G protein-coupled receptor; adenosine receptor; chronic neuropathic pain; crystallographic structure; molecular modeling; purines