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This structure differs from the predominant pharmacophore for most small\u2010molecule CC\u2010chemokine receptor antagonists, which in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold> The compounds were tested as inverse agonists and as antagonists against CCL1\u2010induced activity in G\u03b1<jats:sub>i<\/jats:sub> signalling and chemotaxis. Furthermore, they were assessed by heterologous competition binding against two radiolabelled receptor ligands: the endogenous agonist CCL1 and the virus\u2010encoded antagonist MC148.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold> All compounds were highly potent inverse agonists with EC<jats:sub>50<\/jats:sub> values from 1.7 to 23\u2003nM. Their potencies as antagonists were more widely spread (EC<jats:sub>50<\/jats:sub> values from 5.9 to 1572\u2003nM). Some compounds were balanced antagonists\/inverse agonists whereas others were predominantly inverse agonists with &gt;100\u2010fold lower potency as antagonists. A correspondingly broad range of affinities, which followed the antagonist potencies, was disclosed by competition with [<jats:sup>125<\/jats:sup>I]\u2010CCL1 (K<jats:sub>i<\/jats:sub> 3.4\u2013842\u2003nM), whereas the affinities measured against [<jats:sup>125<\/jats:sup>I]\u2010MC148 were less widely spread (K<jats:sub>i<\/jats:sub> 0.37\u201327\u2003nM), and matched the inverse agonist potencies.<\/jats:p><jats:p><jats:bold>CONCLUSION AND IMPLICATIONS<\/jats:bold> Despite highly potent and direct effects as inverse agonists, competition\u2010binding experiments against radiolabelled agonist and tests for antagonism revealed a probe\u2010dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and divided the compounds into two groups: predominantly inverse agonists and balanced antagonists\/inverse agonists. These studies have important implications for the design of new inverse agonists with or without antagonist properties.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2012.02076.x","type":"journal-article","created":{"date-parts":[[2012,6,19]],"date-time":"2012-06-19T08:34:24Z","timestamp":1340094864000},"page":"1206-1217","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Molecular requirements for inhibition of the chemokine receptor CCR8 \u2013 probe\u2010dependent allosteric 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