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
J Med Chem, 52 (8):
2393-406 (April 2009)Franchetti, Palmarisa Cappellacci, Loredana Vita, Patrizia Petrelli,
Riccardo Lavecchia, Antonio Kachler, Sonja Klotz, Karl-Norbert Marabese,
Ida Luongo, Livio Maione, Sabatino Grifantini, Mario Research Support,
Non-U.S. Gov't United States Journal of medicinal chemistry J Med
Chem. 2009 Apr 23;52(8):2393-406..Zusammenfassung
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.