Delving into the Latest Updates on F-15599 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

F15599, NLX 101, NLX-101

Target

5-HT1A receptor

Mechanism

5-HT1A receptor agonists(Serotonin 1a (5-HT1a) receptor agonists)

Therapeutic Areas

Nervous System DiseasesCongenital DisordersOther Diseases

Active Indication

Fragile X SyndromeRett SyndromeCognition Disorders+ [2]

Inactive Indication

Depressive Disorder

Originator Organization

Pierre Fabre SA

Active Organization

Neurolixis, Inc.

Pierre Fabre SA

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Login to view timeline

Structure

Molecular FormulaC19H21ClF2N4O

InChIKeyWAAXKNFGOFTGLP-UHFFFAOYSA-N

CAS Registry635323-95-4

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) like fluoxetine remain a first-line treatment for major depression, but are effective in less than half of patients and can take 4-8 weeks to show results. In this study, we examined cF1ko mice with genetically induced upregulation of 5-HT1A autoreceptors that reduces 5-HT neuronal activity. These mice display anxiety- and depression-related behaviors that did not respond to chronic fluoxetine treatment. We examined treatment with NLX-101, a biased agonist that preferentially targets 5-HT1A heteroreceptors. By testing different doses of NLX-101, we found that a dose of 0.2 mg/kg was effective in reducing depression-related behavior in cF1ko mice without causing hypothermia, a 5-HT1A autoreceptor-mediated response. After 1 h, this dose activated dorsal raphe 5-HT neurons and cells in the medial prefrontal cortex (mPFC), increasing nuclear c-fos labelling in cF1ko mice. In cF1ko mice but not wild-type littermates, 0.2 mg/kg NLX-101 administered 1 h prior to each behavioral test for two weeks reduced depressive behavior in the forced swim test, but increased anxiety-related behaviors in the open field, elevated plus maze, and novelty suppressed feeding tests. During this treatment, NLX-101 induced widespread increases in the density of 5-HT axons, varicosities, and especially synaptic and triadic structures, particularly in depression-related brain regions including mPFC, hippocampal CA1 and CA2/3, amygdala and nucleus accumbens of cF1ko mice. Overall, NLX-101 was rapid and effective in reducing depressive behavior in SSRI-resistant mice, but also induced anxiety-related behaviors. The increase in serotonin innervation induced by intermittent NLX-101 may contribute to its behavioral actions.

01 Jul 2024·JOURNAL OF PSYCHOPHARMACOLOGY

The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, like ketamine, elicit rapid-acting antidepressant activity in the rat chronic mild stress model via cortical mechanisms

Article

Author: Litwa, Ewa ; Newman-Tancredi, Adrian ; Papp, Mariusz ; Lason, Magdalena ; Gruca, Piotr ; Depoortère, Ronan

Background::

The highly selective 5-HT1A serotonin receptor “biased” agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model with systemic (i.p.) administration. They rapidly (within 1 day) reverse anhedonia (i.e., CMS-induced sucrose consumption deficit), attenuate working memory deficit (novel object recognition: NOR), and decrease anxiety behavior in the elevated-plus maze (EPM).

Aims::

Here, we sought to explore the contribution of prefrontal cortex (PFC) 5-HT1A receptor activation in the RAAD activity of NLX compounds.

Results/Outcomes::

In male Wistar rats, unilateral PFC microinjections of NLX-204 and NLX-101 (16 µg), like ketamine (10 µg), reproduced the effects of their systemic administration: they reversed CMS-induced sucrose consumption deficit, attenuated anxiety (EPM), and reduced working memory deficits (NOR). In addition, unilateral PFC microinjections of the selective 5-HT1A antagonist, WAY-100,635 (2 µg), attenuated the beneficial effects of systemic NLX-204 and NLX-101 (0.16 mg/kg i.p.) in the sucrose intake and NOR models, indicating that these compounds exert their RAAD activity specifically through activation of PFC 5-HT1A receptors.

Conclusions/Interpretation::

These data indicate that 5-HT1A receptor biased agonists share with ketamine a common neuroanatomical site for RAAD activity, which can be obtained not only by targeting glutamatergic/NMDA neurotransmission (ketamine’s primary mechanism of action) but also by activating 5-HT1A receptors, as is the case for the NLX compounds. The present observations also reinforce the notion that biased agonism at 5-HT1A receptors constitutes a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits and anxiety in depressed patients, without ketamine’s troublesome side effects.

01 May 2024·Pharmacology, biochemistry, and behavior

Prevention of MK-801-induced amnestic effect with combined activation of 5-HT1A and muscarinic receptors in mice

Article

Author: Rafało-Ulińska, Anna ; Cieślik, Paulina ; Wierońska, Joanna M

BACKGROUND:

Muscarinic or 5-HT_1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits.

METHODS:

Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT_1A receptor agonist (F15599) alone or in combinations with VU0357017 (M₁ receptor allosteric agonist), VU0152100 (M₄ receptor positive allosteric modulator), and VU0238429 (M₅ receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT_1A receptors and the level of GAD₆₅ in the frontal cortices (FCs) and hippocampi of the animals.

RESULTS:

F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT_1A expression in the hippocampi and decreased GAD₆₅ levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice.

CONCLUSION:

Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT_1A and GAD₆₅ dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.

100 Deals associated with F-15599

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Fragile X Syndrome	Phase 1	US	Neurolixis, Inc.	20 Apr 2023
Rett Syndrome	Phase 1	US	Neurolixis, Inc.	20 Apr 2023
Cognition Disorders	Phase 1	-	Pierre Fabre SA	-
Mood Disorders	Phase 1	-	Pierre Fabre SA	-
Schizophrenia	Phase 1	-	Pierre Fabre SA	-
Depressive Disorder	Preclinical	US	Neurolixis, Inc.	27 Jul 2019