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ACS Med Chem Lett. 2015 May 20;6(7):804-8. doi: 10.1021/acsmedchemlett.5b00150. eCollection 2015 Jul 9.

Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy.

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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.
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine , St. Louis, Missouri 63104, United States.
Department of Pharmacology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, United States.


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.


G protein-coupled receptor; adenosine receptor; chronic neuropathic pain; crystallographic structure; molecular modeling; purines

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