Pharmacological characterizations of the 'legal high' fluorolintane and isomers

Jason Wallach*, Tristan Colestock, Julià Agramunt, Matt Claydon, Michael Dybek, Nathalie Filemban, Muhammad Chatha, Adam L. Halberstadt, Adam L. Halberstadt, Simon Brandt, David Lodge, Zuner A Bortolotto, Adeboye Adejare

*Corresponding author for this work

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Abstract

1,2-Diarylethylamines represent a class of molecules that have shown potential in the treatment of pain, epilepsy, neurodegenerative disease and depression. Examples include lefetamine, remacemide, and lanicemine. Recently, several 1,2-diarylethylamines including the dissociatives diphenidine, methoxphenidine and ephenidine as well as the opioid MT-45, have appeared as ‘research chemicals’ or ‘legal highs’. Due to their recent emergence little is known about their pharmacology. One of these, 1-[1-(2-fluorophenyl)-2-phenylethyl]pyrrolidine (fluorolintane, 2-F-DPPy), is available for purchase with purported dissociative effects intended to resemble phencyclidine (PCP) and ketamine. To better understand this emerging class, pharmacological investigations were undertaken for the first time on fluorolintane and its five aryl-fluorine-substituted isomers. In vitro binding studies revealed high affinity for N-methyl-D-aspartate (NMDA) receptors with fluorolintane (Ki = 87.92 nM) with lesser affinities for related compounds. Additional affinities were seen for all compounds at several sites including norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters, and sigma receptors. Notably high affinities at DAT were observed, which were in most cases greater than NMDA receptor affinities. Additional functional and behavioral experiments show fluorolintane inhibited NMDA receptor-induced field excitatory postsynaptic potentials in rat hippocampal slices and inhibited long-term potentiation induced by theta-burst stimulation in rat hippocampal slices with potencies consistent with its NMDA receptor antagonism. Finally fluorolintane inhibited prepulse inhibition in rats, a measure of sensorimotor gating, with a median effective dose (ED50) of 13.3 mg/kg. These findings are consistent with anecdotal reports of dissociative effects of fluorolintane in humans.
Original languageEnglish
Article number172427
Number of pages9
JournalEuropean Journal of Pharmacology
Volume857
Early online date29 May 2019
DOIs
Publication statusPublished - 15 Aug 2019

Keywords

  • NMDA receptor antagonist
  • legal high
  • fluorolintane
  • diphenidine
  • new psychoactive substance
  • ketamine.

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    Wallach, J., Colestock, T., Agramunt, J., Claydon, M., Dybek, M., Filemban, N., Chatha, M., Halberstadt, A. L., Halberstadt, A. L., Brandt, S., Lodge, D., Bortolotto, Z. A., & Adejare, A. (2019). Pharmacological characterizations of the 'legal high' fluorolintane and isomers. European Journal of Pharmacology, 857, [172427]. https://doi.org/10.1016/j.ejphar.2019.172427