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
journal contributionposted on 05.02.2019, 00:00 by Joanna Sniecikowska, Monika Gluch-Lutwin, Adam Bucki, Anna Więckowska, Agata Siwek, Magdalena Jastrzebska-Wiesek, Anna Partyka, Daria Wilczyńska, Karolina Pytka, Krzysztof Pociecha, Agnieszka Cios, Elżbieta Wyska, Anna Wesołowska, Maciej Pawłowski, Mark A. Varney, Adrian Newman-Tancredi, Marcin Kolaczkowski
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.
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histamine H 15- HT 1dopamine D 2derivativeLELPmuscarinic M 1 receptorsphosphorylationreceptor affinityreceptor-biased agonists-4-ylselectivityβ- arrestin recruitmentpharmacokinetic profileCaco -2 penetrationNLXNovel Aryloxyethyl DerivativesFsp 3rat cortexblock CYP 3A CYP 2D isoenzymesnovel seriesnoradrenergic α 1vivo studiesSafetyScreen 44 panelantidepressant drug candidatesantidepressant-like activityMEDcAMP inhibitionrat Porsolt testsignal transduction assaysERKserotonin 5- HT 2serotonin 5- HT 1druglike propertiesCNS-MPOReceptor-Biased Agonists