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Citation
Tags
HERO ID
6071039
Reference Type
Journal Article
Title
N6-Cycloalkyl- and N6-bicycloalkyl-C5'(C2')-modified adenosine derivatives as high-affinity and selective agonists at the human A1 adenosine receptor with antinociceptive effects in mice
Author(s)
Franchetti, P; Cappellacci, L; Vita, P; Petrelli, R; Lavecchia, A; Kachler, S; Klotz, KN; Marabese, I; Luongo, L; Maione, S; Grifantini, M
Year
2009
Is Peer Reviewed?
Yes
Journal
Journal of Medicinal Chemistry
ISSN:
0022-2623
EISSN:
1520-4804
Volume
52
Issue
8
Page Numbers
2393-2406
Language
English
PMID
19317449
DOI
10.1021/jm801456g
Abstract
To further investigate new potent and selective human A(1) adenosine receptor agonists, we have synthesized a series of 5'-chloro-5'-deoxy- and 5'-(2-fluorophenylthio)-5'-deoxy-N(6)-cycloalkyl(bicycloalkyl)-substituted adenosine and 2'-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A(1), A(2A), A(2B), and A(3) adenosine receptors. In the series of N(6)-cyclopentyl- and N(6)-(endo-norborn-2-yl)adenosine derivatives, 5'-chloro-5'-deoxy-CPA (1) and 5'-chloro-5'-deoxy-(+/-)-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA(1) vs the other human receptor subtypes. The higher affinity and selectivity of 5'-chloro-5'-deoxyribonucleoside derivatives 1 and 3 for hA(1) AR vs hA(3) AR compared to that of the parent 5'-hydroxy compounds CPA and (+/-)-ENBA was rationalized by a molecular modeling analysis. 5'-Chloro-5'-deoxy-(+/-)-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p.
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