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Synthesis and characterization of novel 2-amino-3-benzoylthiophene derivatives as biased allosteric agonists and modulators of the adenosine A(1) receptor

journal contribution
posted on 2012-03-08, 00:00 authored by C Valant, L Aurelio, S M Devine, Trent Ashton, J M White, P M Sexton, A Christopoulos, P J Scammells
A series of novel 2-amino-3-benzoylthiophenes (2A3BTs) were screened using a functional assay of A(1)R mediated phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in intact CHO cells to identify potential agonistic effects as well as the ability to allosterically modulate the activity of the orthosteric agonist, R-PIA. Two derivatives, 8h and 8i, differing only in terms of the absence or presence of an electron-withdrawing group on the benzoyl moiety of the 2A3BT scaffold, were identified as biased allosteric agonists and positive allosteric modulators of agonist function at the adenosine A(1) receptor (A(1)R) in two different functional assays. Our findings indicate that subtle structural variations can promote functionally distinct receptor conformational states.

History

Journal

Journal of medicinal chemistry

Volume

55

Issue

5

Pagination

2367 - 2375

Publisher

American Chemical Society

Location

Easton, Pa.

ISSN

0022-2623

eISSN

1520-4804

Language

eng

Publication classification

C Journal article; C1.1 Refereed article in a scholarly journal

Copyright notice

2012, American Chemical Society