The selective 5-HT1A receptor biased agonists, F15599 and F13714, show antidepressant-like properties after a single administration in the mouse model of unpredictable chronic mild stress

Abstract

Rationale The prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs. Objectives The antidepressant-like and procognitive effects of the “biased agonists” F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT1A receptors and F13714, which targets 5-HT1A autoreceptors, were investigated in mice. Methods Antidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds’ activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) were also determined. Results F15599 reduced immobility time in the FST over a wider dose-range (2 to 16 mg/kg po) than F13714 (2 and 4 mg/kg po), suggesting accentuated antidepressant-like properties in mice. F15599 did not disrupt long-term memory consolidation in the NOR at any dose tested, while F13714 impaired memory formation, notably at higher doses (4–16 mg/kg). In UCMS mice, a single administration of F15599 and F13714 was sufficient to robustly normalize depressive-like behavior in the FST but did not rescue disrupted sucrose preference. Both F15599 and F13714 rescued cortical and hippocampal deficits in p-ERK1/2 levels of UCMS mice but did not influence the p-CREB levels. Conclusions Our studies showed that 5-HT1A receptor biased agonists such as F13714 and especially F15599, due to its less pronounced side effects, might have potential as fast-acting antidepressants.

The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, display ketamine-like RAAD and anti-TRD activities in rat CMS models

“…More generally, the present data for NLX-204 extend its profile of activity in preclinical models of depression. The compound is potently and efficaciously active upon acute administration in the FST in naïve rats (Sniecikowska et al 2019 ), and displays RAAD-like activity in the CMS and chronic corticosterone assays in mice (Głuch-Lutwin et al 2021 ).…”

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“…F15599 and F13714 ( 56 and 57 , Figure ) are biased agonists of 5-HT 1A receptors and possess antidepressant- and anxiolytic-like properties in rats. ,− F15599 preferentially acts on postsynaptic 5-HT 1A receptors in the brain regions, such as the prefrontal cortex, while F13714 is a preferential agonist at presynaptic autoreceptors in the raphe nuclei. As a result, the radioligands [ 18 F] 56 and [ 18 F] 57 displayed distinct binding patterns in the living brain (section ).…”

Molecular Signaling Mechanisms for the Antidepressant Effects of NLX-101, a Selective Cortical 5-HT1A Receptor Biased Agonist

“…Recent preclinical studies have demonstrated that the administration of the highly selective 5-HT 1A receptor biased agonist, NLX-101 (also known as F15599), results in a rapid antidepressant-like response, both in naïve animals [ 12 , 13 ] and rodent models of depression [ 14 , 15 ], presumably through the activation of cortical 5-HT 1A receptors. Indeed, direct cortical microinjection of NLX-101 reduced immobility in the forced swim test, an effect that was blocked by the selective 5-HT 1A receptor antagonist, WAY-100635 [ 16 ].…”