5'-substituted adenosine analogs as new high-affinity partial agonists for the adenosine A1 receptor

Journal of Medicinal Chemistry
E M Van der WendenAd P IJzerman

Abstract

5'-(Alkylthio)-, 5'-(methylseleno)-, and 5'-(alkylamino)-substituted analogues of N6-cyclopen-tyladenosine (CPA) were synthesized in 30-50% overall yields. The affinities of these compounds for the adenosine A1 and A2A receptors were determined in rat brain membranes. The 5'-substituted CPA analogues proved selective for the adenosine A1 receptors, displaying affinities in the nanomolar range. The compounds were also evaluated for their ability to stimulate [35S]GTP gamma S binding, also in rat brain membranes. The Ki values in receptor binding studies corresponded well to the EC50 values thus obtained. Intrinsic activities of the compounds were tested in vitro by determining the GTP shift in receptor binding studies as well as the maximal binding of [35S]GTP gamma S. It appeared that the 5'-thio and 5'-seleno derivatives in particular behaved as partial agonists.

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Citations

Mar 1, 2012·Purinergic Signalling·Kenneth A JacobsonZhan-Guo Gao
Nov 5, 1999·Trends in Pharmacological Sciences·H P van Helden, T J Bueters
Apr 26, 2003·Bioorganic & Medicinal Chemistry·Erica W van TilburgAd P IJzerman
Jun 8, 2000·Journal of Medicinal Chemistry·K A JacobsonR G Ravi
Mar 22, 2005·Nucleic Acids Research·Lindsay R Comstock, Scott R Rajski
Jun 24, 2006·Bioorganic & Medicinal Chemistry Letters·T D Ashton, Peter J Scammells
Jul 2, 2005·Bioorganic & Medicinal Chemistry Letters·Maykel Pérez GonzálezMaria J González-Moa
Nov 5, 2016·Journal of Pharmacological and Toxicological Methods·François Noël, Fernando M do Monte
Dec 10, 2003·Expert Opinion on Emerging Drugs·Luo YanChrista E Müller
Feb 14, 2004·The Journal of Organic Chemistry·Lindsay R Comstock, Scott R Rajski
Apr 23, 1999·Journal of Medicinal Chemistry·M de ZwartA P IJzerman

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