NLX-204 hydrochloride

NLX-204 (hydrochloride) is an orally active, potent, highly affinity and selective 5-HT1A receptor-biased agonist (pKi=10.19). NLX-204 (hydrochloride) shows relatively higher affinity for α1 and D2 receptors than for other off-targets. NLX-204 (hydrochloride) can be used for the research of antidepressant[1].

NLX-204 (10 μM) (hydrochloride) shows substantial binding inhibition (higher than 50%) for adrenergic α1A and α2A and dopaminergic D2S receptors. NLX-204 (1 μM) (hydrochloride) exhibits much lower binding inhibition at D2 and α2A receptors but maintains a relatively high value for the α1Areceptor. NLX-204 (0.1~10 μM) (hydrochloride) has a low propensity for hERG channel blockade and suggests that the investigated series has a low risk with respect to hERG-related cardiac safety. NLX-204 (hydrochloride) also exhibits high microsomal stability. NLX-204 (hydrochloride) displays no P-gp inhibition (6.5% of inhibition at 10 μM) as well as negligible inhibition of CYP3A4 and CYP2D6 (23.2 and 15.9% at 10 μM, respectively). NLX-204 (hydrochloride) does not elicit flat body posture (FBP), a common side effect of the 5-HT1A receptor stimulation, suggesting that its preference for activation of 5-HT1A receptor-mediated ERK1/2 phosphorylation in vitro translates to preferential antidepressant effects rather than induction of "behavioral syndrome"[1].

NLX-204 (2.5 mg/kg; p.o.) (hydrochloride) is rapidly absorbed from the gastrointestinal tract (Tmax = 15 min), reaches relatively high serum concentrations and shows higher concentration than those in serum for all doses[1].NLX-204 (0.04~2.5 mg/kg; p.o.) (hydrochloride) shows that statistically significant elevation of pERK1/2 is observed at the two highest doses (2.5 and 0.63 mg/kg), but a tendency to increase pERK1/2 levels is also seen at lower doses[1].NLX-204 (hydrochloride) robustly and significantly increases rat PFC ERK1/2 phosphorylation in a time dependent manner[1].

[1]. Sniecikowska J, et al. Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT1A Receptor-Biased Agonists with Robust Antidepressant-like Activity. J Med Chem. 2019;62(5):2750-2771.