Molecular requirements for CCR8 receptor inhibition- Probe-dependent allosteric interactions.
Summary of "Molecular requirements for CCR8 receptor inhibition- Probe-dependent allosteric interactions."
Here we present a novel series of CCR8 antagonists based on a naphthalene-sulfonamide structure. This structure differs from the predominant pharmacophore for most small-molecule CC-chemokine receptor antagonists, that in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes. EXPERIMENTAL
The compounds were tested as inverse agonists and as antagonists against CCL1-induced activity in Gαi signaling and chemotaxis. Furthermore, they were subjected to heterologous competition binding against two radiolabeled chemokines: the endogenous agonist CCL1 and the virus-encoded antagonist MC148. KEY
All compounds acted as high-potent inverse agonists with EC(50) values from 1,7 to 23 nM. Their potencies as antagonists were however far more diverse with EC(50) values from 5,9 to 1572 nM. Some compounds were balanced antagonists/inverse agonists, whereas others were predominant inverse agonists with >100-fold lower potency as antagonists as compared to inverse agonists. A corresponding broad range of affinities, that followed the antagonistic potencies, was observed in competition with (125) I-CCL1 (Ki from 3.4 to 842 nM), whereas the affinities measured against (125) I-MC148 were more similar (Ki from 0.37 to 27 nM), and matched the inverse agonistic potencies. CONCLUSION AND
Despite high-potency direct effects as inverse agonists, competition binding experiments against radiolabeled agonist and tests for antagonism revealed a probe dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and thereby divided the compounds into two groups: predominant inverse agonists and balanced antagonists/inverse agonists. These studies have huge implications for future design inverse agonists with/without antagonistic properties. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Department of Neuroscience and Pharmacology, Faculty of Health Sciences, Copenhagen University, Copenhagen, Denmark. Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, Universität Leipzig, Germany. Millennium Pharmaceuticals, Cam
This article was published in the following journal.
Name: British journal of pharmacology
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22708643
- DOI: http://dx.doi.org/10.1111/j.1476-5381.2012.02076.x
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