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Selective A3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system

Melman, Artem and Wang, Ben and Joshi, Bhalchandra V. and Gao, Zhan-Guo and de Castro, Sonia and Heller, Cara L. and Kim, Soo-Kyung and Jeong, Lak Shin and Jacobson, Kenneth A. (2008) Selective A3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system. Bioorganic and Medicinal Chemistry, 16 (18). pp. 8546-8556. ISSN 09680896. http://resolver.caltech.edu/CaltechAUTHORS:MELbmc08

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Abstract

We have prepared 5′-modified derivatives of adenosine and a corresponding (N)-methanocarba nucleoside series containing a bicyclo[3.1.0]hexane ring system in place of the ribose moiety. The compounds were examined in binding assays at three subtypes of adenosine receptors (ARs) and in functional assays at the A3 AR. The H-bonding ability of a group of 9-riboside derivatives containing a 5′-uronamide moiety was reduced by modification of the NH; however these derivatives did not display the desired activity as selective A3 AR antagonists, as occurs with 5′-N,N-dimethyluronamides. However, truncated (N)-methanocarba analogues lacking a 4′-hydroxymethyl group were highly potent and selective antagonists of the human A3 AR. The compounds were synthesized from d-ribose using a reductive free radical decarboxylation of a 5′-carboxy intermediate. A less efficient synthetic approach began with L-ribose, which was similar to the published synthesis of (N)-methanocarba A3AR agonists. Compounds 33b–39b (N6-3-halobenzyl and related arylalkyl derivatives) were potent A3AR antagonists with binding Ki values of 0.7–1.4 nM. In a functional assay of [35S]GTPγS binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a KB of 8.9 nM. Thus, a highly potent and selective series of A3AR antagonists has been described.


Item Type:Article
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URLURL TypeDescription
http://dx.doi.org/10.1016/j.bmc.2008.08.007DOIUNSPECIFIED
Additional Information:Copyright © 2008 Elsevier. Received 16 June 2008; revised 1 August 2008; accepted 4 August 2008. Available online 7 August 2008. We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases.
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Funding AgencyGrant Number
National Institute of Diabetes and Digestive and Kidney DiseasesUNSPECIFIED
Subject Keywords:G protein-coupled receptor; Purines; Molecular modeling; Structure–activity relationship; Radioligand binding; Adenylate cyclase
Record Number:CaltechAUTHORS:MELbmc08
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:MELbmc08
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ID Code:11917
Collection:CaltechAUTHORS
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Deposited On:09 Oct 2008 22:24
Last Modified:26 Dec 2012 10:23

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