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.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Tosh DK,Crane S,Chen Z,Paoletta S,Gao ZG,Gizewski E,Auchampach JA,Salvemini D,Jacobson KAdoi
10.1021/acsmedchemlett.5b00150subject
Has Abstractpub_date
2015-05-20 00:00:00pages
804-8issue
7issn
1948-5875journal_volume
6pub_type
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journal_title:ACS medicinal chemistry letters
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