Fentanyl-related designer drugs W-18 and W-15 lack appreciable opioid activity in vitro and in vivo
Xi-Ping Huang, Tao Che, Thomas J. Mangano, Valerie Le Rouzic, Ying-Xian Pan, Susruta Majumdar, Michael D. Cameron, Michael H. Baumann, Gavril W. Pasternak, Bryan L. Roth
Xi-Ping Huang, Tao Che, Thomas J. Mangano, Valerie Le Rouzic, Ying-Xian Pan, Susruta Majumdar, Michael D. Cameron, Michael H. Baumann, Gavril W. Pasternak, Bryan L. Roth
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Research Article Neuroscience

Fentanyl-related designer drugs W-18 and W-15 lack appreciable opioid activity in vitro and in vivo

Abstract

W-18 (4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide) 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, as examination of their structural features predicted that they might lack opioid activity. We found W-18 and W-15 to be without detectible 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 GPCRs in the human genome using the PRESTO-Tango platform revealed no significant activity. Weak activity at the sigma receptors and the peripheral benzodiazepine receptor was found for W-18 (Ki = 271 nM). W-18 showed no activity in either the radiant heat tail-flick or the writhing assays and also did not induce classical opioid behaviors. W-18 is extensively metabolized, but its metabolites also lack opioid activity. 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.

Authors

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

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Figure 10

Analgesic activity of W-18 in tail-flick and writhing assays.

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Analgesic activity of W-18 in tail-flick and writhing assays. (A) Radian...
(A) Radiant heat tail-flick: W-18 was tested in the radiant heat tail-flick assay at 0.1 and 1 mg/kg, s.c., as previously described (25). Groups of mice (n = 10) received the indicated dose of W-18, after determining baseline latencies, and were tested at the indicated times. ANOVA revealed no significant differences among groups or times. W-18 (0.1 mg/ml) was dissolved in DMSO (10%), Tween 80 (10%)/water for use at the 1 mg/kg dose. The solution was diluted 10-fold to 0.01 mg/ml for use in the 0.1 mg/kg dose. (B) Acetic acid–induced writhing: groups of mice (n = 10) received either saline or W-18 (1 mg/kg, s.c.). Fifteen minutes later, all mice received 1% acetic acid (10 μl/g), and writhes were counted from 5–15 minutes after acetic acid injection. There were no significant differences between the groups by Student’s t test.