NLX-204

NLX-101 and NLX-204 are highly selective serotonin 5-HT_1A 'biased' agonists, displaying potent and efficacious antidepressant-like activity upon acute administration in models such as the forced swim test.

we compared the effects of repeated administration of NLX-101, NLX-204 and ketamine in the chronic mild stress (CMS) model of depression, considered to have high translational potential, on sucrose consumption (anhedonia measure), novel object recognition (NOR; working memory measure) and elevated plus maze (EPM; anxiety measure) in male Wistar and Wistar-Kyoto rats (the latter being resistant to classical antidepressants).

in Wistar rats, NLX-204 and NLX-101 (0.08-0.16 mg/kg i.p.), like ketamine (10 mg/kg i.p.) dose-dependently reversed CMS-induced sucrose intake deficit from treatment Day 1, with nearly full reversal observed at the higher dose at Days 8 and 15. These effects persisted for 3 weeks following treatment cessation. In the NOR test, both doses of NLX-101/NLX-204, and ketamine, rescued the deficit in discrimination index caused by CMS on Days 3 and 17; all three compounds increased time spent in open arms (EPM) but only NLX-204 achieved statistical significance on Days 2 and 16. In Wistar-Kyoto rats, all 3 compounds were also active in the sucrose test and, to a lesser extent, in the NOR and EPM. In non-stressed rats (both strains), the three compounds produced no significant effects in all tests.

these observations further strengthen the hypothesis that biased agonism at 5-HT_1A receptors constitutes a promising strategy to achieve rapid-acting/sustained antidepressant effects combined with activity against TRD, in addition to providing beneficial effects against memory deficit and anxiety in depressed patients.

Activation of cortical serotonin 5-HT_1A receptors may be a promising strategy to achieve rapid-acting antidepressant (RAAD) activity. NLX-204 is a selective 5-HT_1A receptor biased agonist that, in naïve mice, robustly decreases immobility in the forced swim test (FST), and preferentially phosphorylates extracellular signal-regulated kinase (ERK1/2), involved in antidepressant activity. Here, we evaluated the properties of NLX-204 in two mouse models of depression. Male CD-1 mice were subjected to unpredictable chronic mild stress (UCMS) for 4-weeks or to repeated corticosterone (CORT, 20 mg/kg s.c./day) for 3-weeks before receiving acute administration of NLX-204 (2 mg/kg, p.o.). Depressive-like behavior was assessed in the FST, anhedonia-like behavior in the sucrose preference test (SPT) and locomotor activity was also recorded. Phosphorylation of ERK1/2 (pERK1/2) and cAMP response binding element (pCREB) were measured ex vivo in hippocampus and prefrontal cortex (PFC). UCMS or CORT treatment increased immobility in the FST, elicited a sucrose preference deficit, and decreased pERK1/2 and pCREB levels in PFC and hippocampus. NLX-204 reduced depressive-like behavior in the FST in CORT and UCMS mice, and normalized sucrose preference in CORT mice, suggesting anti-anhedonic activity. NLX-204 increased pERK1/2 levels in PFC of UCMS mice. NLX-204 also increased pCREB levels in PFC of CORT mice. These data suggest that NLX-204 has RAAD-like properties not only in naïve mice, but also in mice in a "depressive-like" state, and that these involve changes in PFC and hippocampal pERK1/2 and pCREB levels. These data provide additional evidence that activation of 5-HT_1A receptors by selective biased agonists, such as NLX-204, may constitute a promising RAAD strategy.