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New 2,N6-Disubstituted adenosines: Potent and selective A1 adenosine receptor agonists

Version 2 2024-06-17, 03:56
Version 1 2014-10-27, 16:27
journal contribution
posted on 2024-06-17, 03:56 authored by S Hutchinson, S Baker, P Scammells
A number of adenosine analogues substituted in the 2- and N6-positions were synthesized and evaluated for affinity, functional potency and intrinsic activity at the A1 and A2A adenosine receptors (AR). Three classes of N6-substituents were tested; norbornen-2-yl (series 1), norborn-2-yl (series 2) and 5,6-epoxynorborn-2-yl (series 3). The halogens; fluoro, bromo, and iodo were evaluated as C-2 substituents. All compounds showed relatively high affinity (nanomolar) for the A1AR and high potency for inhibiting (−)isoproterenol-stimulated cAMP accumulation in hamster smooth muscle DDT1 MF-2 cells with the 2-fluoro derivatives from each series having the highest affinity. All of the derivatives showed the same intrinsic activity as CPA. At the A2AAR, all of the derivatives showed relatively low affinity and potency (micromolar) for stimulating cAMP accumulation in rat pheochromocytoma PC-12 cells. The intrinsic activity of the derivatives compared to CGS 21680 was dependent upon the halogen substituent in the C-2 position with most showing partial agonist activity. Of particular interest is 2-iodo-N6-(2S-endo-norborn-2-yl)adenosine (5e), which is over 100-fold selective for the A1AR, is a full agonist at this receptor subtype and has no detectable agonist activity at the A2AAR.

History

Alternative title

New 2,N6-Disubstituted adenosines: Potent and selective A1 adenosine receptor agonists

Journal

Bioorganic & medicinal chemistry

Volume

10

Pagination

1115-1122

Location

Oxford, England

ISSN

0968-0896

eISSN

1464-3391

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

2002, Elsevier Science Ltd.

Issue

4

Publisher

Pergamon

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