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

Department of Chemical Sciences, University of Camerino, 62032 Camerino, Italy.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 04/2009; 52(8). DOI: 10.1021/jm801456g


To further investigate new potent and selective human A1 adenosine receptor agonists, we have synthesized a series of 5′-chloro-5′-deoxy- and 5′-(2-fluorophenylthio)-5′-deoxy-N6-cycloalkyl(bicycloalkyl)-substituted adenosine and 2′-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A1, A2A, A2B, and A3 adenosine receptors. In the series of N6-cyclopentyl- and N6-(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 hA1 vs the other human receptor subtypes. The higher affinity and selectivity of 5′-chloro-5′-deoxyribonucleoside derivatives 1 and 3 for hA1 AR vs hA3 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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    • "The following pharmacological agents were used (from Sigma- Aldrich, Milan, Italy): (5R,10S)-(−)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cylcohepten-5,10-imine maleate (MK-801), 6-cyano-7- nitroquinoxaline-2,3-dione disodium salt hydrate (CNQX), papaverine, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), SCH 23390, (±)-1-phe- nyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide (SKF 38393), 6-chloro-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine- 7,8-diol (SKF 81297), 6-hydroxydopamine hydrochloride (6-OHDA), and 3,4-dihydroxy-L-phenylalanine (L-DOPA) (administered i.p. together with benserazide hydrochloride). AE90074 was a kind gift of Dr Jan Kehler, Lundbeck (Copenhagen, Denmark) and N 6 -(±)-endo-norbornyl- 9H-(5-chloro-5-deoxy-β-D-ribofuranosyl)adenine (5′-chloro-5′-deoxy- (±)-ENBA, 5′Cl5′d-(±)-ENBA) was synthesized at the University of Camerino, as previously reported (Franchetti et al., 2009). All drugs used in the electrophysiological experiments were bath applied, while those for the behavioral experiments were dissolved in saline and injected i.p. in a volume of 10 ml/kg, except for 5′Cl5′d-(±)-ENBA that was dissolved in 5% DMSO. "
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