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

• Published in: Journal of medicinal chemistry 2019-03, Vol.62 (5), p.2750-2771
• Main Authors: Sniecikowska, Joanna, Gluch-Lutwin, Monika, Bucki, Adam, Więckowska, Anna, Siwek, Agata, Jastrzebska-Wiesek, Magdalena, Partyka, Anna, Wilczyńska, Daria, Pytka, Karolina, Pociecha, Krzysztof, Cios, Agnieszka, Wyska, Elżbieta, Wesołowska, Anna, Pawłowski, Maciej, Varney, Mark A, Newman-Tancredi, Adrian, Kolaczkowski, Marcin
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00062

Novel 1-(1-benzoylpiperidin-4-yl)­methanamine derivatives were designed as “biased agonists” of serotonin 5-HT1A receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca2+ mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT1A receptor affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, serotonin 5-HT2A, histamine H1, and muscarinic M1 receptors, and favorable druglike properties (CNS-MPO, Fsp3, LELP). The lead structure, (3-chloro-4-fluorophenyl)­(4-fluoro-4-(((2-(pyridin-2-yloxy)­ethyl)­amino)­methyl)­piperidin-1-yl)­methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT1A receptor-biased agonists could constitute promising antidepressant drug candidates.