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9-Ethyladenine derivatives as adenosine receptor antagonists: 2- and 8-substitution results in distinct selectivities

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Abstract

9-Ethyladenine was used as the basis for a series of non-xanthine adenosine receptor antagonists at human adenosine receptors. The adenine-based compounds were substituted in 2- or 8-position with a variety of side chains including some aryl or arylalkynyl groups previously tested as 2-substituents in adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) for their effect on agonist affinity. The affinity of the novel compounds was tested in radioligand binding assays (A1, A2A and A3) and inhibition of NECA-stimulated adenylyl cyclase activity (A2B) in membranes prepared from CHO cells stably transfected with the respective human receptor subtype. High affinity antagonists were identified for A1 (9-ethyl-8-phenyl-9H-adenine, compound 2; 6-(1-butylamino)-9-ethyl-8-phenyl-9H-purine, compound 3), A2A (8-ethoxy-9-ethyladenine; compound 8) and A3 (9-ethyl-8-phenylethynyl-9H-adenine, compound 5) with selectivities versus other receptor subtypes in the range of 10 to 600. These results demonstrate that adenine is a useful template for further development of high-affinity antagonists with distinct receptor selectivity profiles.

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Acknowledgement

This study was supported by the BIOMED 2 program EURCAR (BMH4-CT98-3474).

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Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078, Würzburg, Germany

    Karl-Norbert Klotz & Sonja Kachler

  2. Dipartimento di Science Chimiche, Università degli Studi di Camerino, Via S. Agostino 1, 62032, Camerino, Italy

    Catia Lambertucci, Sauro Vittori, Rosaria Volpini & Gloria Cristalli

Authors
  1. Karl-Norbert Klotz
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  2. Sonja Kachler
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  3. Catia Lambertucci
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  4. Sauro Vittori
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  5. Rosaria Volpini
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  6. Gloria Cristalli
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Correspondence to Karl-Norbert Klotz.

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Klotz, KN., Kachler, S., Lambertucci, C. et al. 9-Ethyladenine derivatives as adenosine receptor antagonists: 2- and 8-substitution results in distinct selectivities. Naunyn-Schmiedeberg's Arch Pharmacol 367, 629–634 (2003). https://doi.org/10.1007/s00210-003-0749-9

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