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.
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.
authors.affiliation: Department of Chemical Sciences, University of Camerino, 62032 Camerino, Italy.
authors.forename: Palmarisa
authors.initials: P
authors.lastname: Franchetti
authors.forename: Loredana
authors.initials: L
authors.lastname: Cappellacci
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vita
authors.forename: Riccardo
authors.initials: R
authors.lastname: Petrelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Sonja
authors.initials: S
authors.lastname: Kachler
authors.forename: Karl-Norbert
authors.initials: KN
authors.lastname: Klotz
authors.forename: Ida
authors.initials: I
authors.lastname: Marabese
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Mario
authors.initials: M
authors.lastname: Grifantini