Cortical 5-hydroxytryptamine 1A receptor biased agonist, NLX-101, displays rapid-acting antidepressant-like properties in the rat chronic mild stress model

J Psychopharmacol. 2019 Nov;33(11):1456-1466. doi: 10.1177/0269881119860666. Epub 2019 Jul 10.


Background: NLX-101 (also known as F15599) is a highly selective and efficacious 'biased' agonist at cortical 5-hydroxytryptamine 1A (5-HT1A) heteroreceptors. In rodents, it possesses marked antidepressant-like activity, potently and completely abolishing immobility in the forced swim test (FST) with extended duration of action.

Methods: We investigated the antidepressant-like activity of NLX-101 using the rat chronic mild stress (CMS) model of depression, considered to have a higher translational potential than the FST, as it possesses construct, face and predictive validity. The effects of CMS and repeated NLX-101 treatment were tested using sucrose consumption (a measure of anhedonia), novel object recognition (NOR; a measure of working memory) and elevated plus maze (EPM; a measure of anxiety) tests.

Results: NLX-101 reversed the CMS-induced decrease of sucrose intake on day 1 of testing, with full reversal observed at the dose of 0.16 mg/kg and a less pronounced but still significant effect at 0.04 mg/kg, both given twice a day intraperitoneally. The effects of NLX-101 were maintained over the 2 week treatment period and persisted for four weeks following cessation of treatment. In the NOR test, both doses of NLX-101 rescued the deficit in discrimination index caused by CMS, without any effect on locomotor activity. However, NLX-101 had no effect on the reduction of open-arms entries produced by CMS in the EPM model. In control, non-stressed rats, NLX-101 produced non-significant effects in all three models.

Conclusions: NLX-101 displayed efficacious activity in the CMS test, with more rapid (1 day) antidepressant-like effects than pharmacological compounds tested previously under the same experimental conditions. These observations suggest that biased agonist targeting of cortical 5-HT1A receptors constitutes a promising strategy to achieve rapid-acting and sustained antidepressant effects.

Keywords: 5-HT1A receptors; Serotonin; biased agonist; chronic mild stress; depression; rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology*
  • Depression / drug therapy*
  • Depression / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Male
  • Maze Learning / drug effects
  • Piperidines / administration & dosage
  • Piperidines / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Wistar
  • Serotonin 5-HT1 Receptor Agonists / administration & dosage
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • Stress, Psychological / drug therapy
  • Stress, Psychological / physiopathology
  • Swimming


  • 3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
  • Antidepressive Agents
  • Piperidines
  • Pyrimidines
  • Serotonin 5-HT1 Receptor Agonists