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By Xi-Ping Huang, Tao Che, Thomas J Mangano, Valerie Le Rouzic, Ying-Xian Pan, Susruta Majumdar, Michael Cameron, Michael Bauman, Gavril W. Pasternak, Bryan L. Roth

Posted 24 Jul 2016
bioRxiv DOI: 10.1101/065623 (published DOI: 10.1172/jci.insight.97222)

W-18 (1-(4-Nitrophenylethyl)piperidylidene-2-(4-chlorophenyl)sulfonamide) and W-15 (4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide) represent two emerging drugs of abuse chemically related to the potent opioid agonist fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylpropanamide). Here we describe the comprehensive pharmacological profiles of W-18 and W-15. Although W-18 and W-15 have been described as having potent anti-nociceptive activity and are presumed to interact with opioid receptors, we found them to be without detectible opioid activity at μ, δ, κ and nociception opioid receptors in a variety of assays. We also tested W-18 and W-15 for activity as allosteric modulators at opioid receptors and found them devoid of significant positive or negative allosteric modulatory activity. Comprehensive profiling at essentially all the druggable G-protein coupled receptors in the human genome using the PRESTO-Tango platform revealed no significant activity. In silico predictions using the Similarity Ensemble Approach suggested activity for W-18 only weakly at H3-histamine receptors, which was not confirmed in radioligand binding studies. Weak activity at the sigma receptors and the peripheral benzodiazepine receptor were found for W-18 (Ki=271 nM); W-15 displayed weak antagonist activity at 5-HT2-family serotonin receptors. W-18 is extensively metabolized, but its metabolites also lack opioid activity. W-18 and W-15 did inhibit hERG binding suggesting possible cardiovascular side-effects with high doses. Thus although W-18 and W-15 have been suggested to be potent opioid agonists, our results reveal no significant activity at these or other known targets for psychoactive drugs.

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