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<p>Psychedelics have garnered significant interest for their therapeutic potential in mental health conditions such as depression, anxiety, and post-traumatic stress disorder. While research has primarily focused on well-studied psychedelics, phenethylamine derivatives have also gathered interest for their potential therapeutic applications. Thus, this study aims to investigate the pharmacological profile, safety and therapeutic potential of novel <i>N</i>-(2-fluorobenzyl) phenethylamine analogs (NBFs) of the 2C-X series—25C-NBF, 25B-NBF, and 25I-NBF. NBFs displayed high affinity and selectivity for the 5-HT<sub>2A</sub> receptor and demonstrated bias factors (defined in our study as the preference for G<sub>q</sub> over β-arrestin pathways at 5-HT<sub>2A</sub> receptor) similar to that of 5-HT. Acute administration induced moderate head-twitch responses without affecting locomotion or pre-pulse inhibition. Our studies revealed no rewarding effects in mice nor reinforcing effects or changes in accumbal dopamine levels in rats after NBFs administration. Further characterization of 25C-NBF revealed psychoplastogenic effects (dendritogenesis, spinogenesis and increased <i>Bdnf</i> mRNA levels) both in vitro and in vivo. In addition, 25C-NBF reduced despair-like behavior in response to acute stress and exerted rapid antidepressant effects in a model of anhedonia-like behavior induced by chronic corticosterone administration. Taken together, these findings suggest that 25C-NBF, and further analogs, may hold potential as novel antidepressants with a rapid onset of action and a favorable safety profile in terms of no abuse potential or sensorimotor gating deficits.</p>

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The psychedelic phenethylamine 25C-NBF, a selective 5-HT2A agonist, shows psychoplastogenic properties and rapid antidepressant effects in male rodents

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Núria Nadal-Gratacós,
  • Pol Puigseslloses,
  • Laura Guzmán,
  • Nicola Weiss,
  • Eline Pottie,
  • Clara Riera-Colomer,
  • Virginie Lardeux,
  • Nathalie Thiriet,
  • Fu-Hua Wang,
  • Liselott Källsten,
  • Irene Pérez-Esteban,
  • Gabriel Ketsela,
  • Joel Margall,
  • Xavier Berzosa,
  • David Pubill,
  • Marta Rodríguez-Arias,
  • Miren Ettcheto,
  • Jan Kehr,
  • Christophe Stove,
  • Marcello Solinas,
  • Harald H. Sitte,
  • Elena Escubedo,
  • Raul López-Arnau

摘要

Psychedelics have garnered significant interest for their therapeutic potential in mental health conditions such as depression, anxiety, and post-traumatic stress disorder. While research has primarily focused on well-studied psychedelics, phenethylamine derivatives have also gathered interest for their potential therapeutic applications. Thus, this study aims to investigate the pharmacological profile, safety and therapeutic potential of novel N-(2-fluorobenzyl) phenethylamine analogs (NBFs) of the 2C-X series—25C-NBF, 25B-NBF, and 25I-NBF. NBFs displayed high affinity and selectivity for the 5-HT2A receptor and demonstrated bias factors (defined in our study as the preference for Gq over β-arrestin pathways at 5-HT2A receptor) similar to that of 5-HT. Acute administration induced moderate head-twitch responses without affecting locomotion or pre-pulse inhibition. Our studies revealed no rewarding effects in mice nor reinforcing effects or changes in accumbal dopamine levels in rats after NBFs administration. Further characterization of 25C-NBF revealed psychoplastogenic effects (dendritogenesis, spinogenesis and increased Bdnf mRNA levels) both in vitro and in vivo. In addition, 25C-NBF reduced despair-like behavior in response to acute stress and exerted rapid antidepressant effects in a model of anhedonia-like behavior induced by chronic corticosterone administration. Taken together, these findings suggest that 25C-NBF, and further analogs, may hold potential as novel antidepressants with a rapid onset of action and a favorable safety profile in terms of no abuse potential or sensorimotor gating deficits.