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Structure−Activity Relationships of Adenine and Deazaadenine Derivatives as Ligands for Adenine Receptors, a New Purinergic Receptor Family

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PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
Dipartimento di Scienze Chimiche, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
§ Latvian Institute of Organic Synthesis, Aizkraukles iela 21, Riga LV-1006, Latvia
*To whom correspondence should be addressed. Phone: +49-228-73-2301. Fax: +49-228-73-2567. E-mail: [email protected]
Cite this: J. Med. Chem. 2009, 52, 19, 5974–5989
Publication Date (Web):September 4, 2009
https://doi.org/10.1021/jm9006356
Copyright © 2009 American Chemical Society

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    Abstract

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    Adenine derivatives bearing substituents in the 2-, N6-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [3H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure−activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure−affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N6-acetyladenine (25, Ki rat: 2.85 μM; Ki human: 0.515 μM) and 8-aminoadenine (33, Ki rat: 6.51 μM; Ki human: 0.0341 μM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family.

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    Elemental analysis data of all tested compounds; information and data on syntheses, yields, melting points, NMR, and LC/ESI-MS spectra of the tested compounds that have previously been described in the literature. This material is available free of charge via the Internet at http://pubs.acs.org.

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