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

JCI Insight. 2017 Nov 16;2(22):e97222. doi: 10.1172/jci.insight.97222.


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.

Keywords: Drug screens; Drug therapy; Neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid
  • Animals
  • Designer Drugs / chemistry*
  • Designer Drugs / pharmacology*
  • Drug Evaluation, Preclinical
  • Fentanyl / chemistry*
  • Fentanyl / pharmacology*
  • HEK293 Cells
  • Humans
  • Illicit Drugs
  • Mice
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB2 / drug effects
  • Receptors, Opioid / drug effects
  • Receptors, Serotonin / drug effects


  • Analgesics, Opioid
  • Designer Drugs
  • Illicit Drugs
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Receptors, Opioid
  • Receptors, Serotonin
  • Fentanyl