Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT_1A Receptor-Biased Agonists with Robust Antidepressant-like Activity

Abstract

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT 1A receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca 2+ mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT 1A receptor affinity, >1000-fold selectivity versus noradrenergic α 1 , dopamine D 2 , serotonin 5-HT 2A , histamine H 1 , and muscarinic M 1 receptors, and favorable druglike properties (CNS-MPO, Fsp 3 , 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-HT 1A receptor-biased agonists could constitute promising antidepressant drug candidates.

Cortical 5-hydroxytryptamine 1A receptor biased agonist, NLX-101, displays rapid-acting antidepressant-like properties in the rat chronic mild stress model

“…NLX-101 (also known as F15599; Maurel et al, 2007), is an exceptionally selective agonist that preferentially activates 5-HT 1A heteroreceptors in cortical regions versus 5-HT 1A autoreceptors in Raphe nuclei, as observed in electrophysiology, neurochemistry and brain imaging (pharmacologic magnetic resonance imaging MRI and positron emission tomography) studies (Becker et al, 2016; Llado-Pelfort et al, 2010). This first-in-class profile appears to arise from NLX-101’s marked biased agonism for ERK phosphorylation versus other signalling pathways, including cyclic AMP inhibition, receptor internalisation, beta-arrestin activation or Ca 2+ release (Newman-Tancredi, 2011; Newman-Tancredi et al, 2009; Sniecikowska et al, 2019). Further, NLX-101 also preferentially activates ERK phosphorylation ex vivo in the frontal cortex versus dorsal or medial Raphe nucleus but, unlike ketamine, does not influence ERK phosphorylation in hippocampus (Haiying et al, 2017; Newman-Tancredi et al, 2009).…”

Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

“…Interestingly, the 2-pyrazine substituent (ring B) maintained the desired level of affinity (pK i > 8) and the effect of the alkyl substituent at the 5-position of the ring B exhibited difference. [106,107]…”

“…Subsequently, taking 35 as a lead compound, the same research group synthesized a series of novel 1‐(1‐benzoylpiperidin‐4‐yl)methanamine derivatives and tested their comprehensive functional selectivity profiles in signal transduction assays. [ 107 ] Among all the derivatives, NLX‐204 ( 36 , Figure 6) showed a high 5‐HT 1A receptor affinity with a p K i value of 10.19 and displayed high selectivity in the SafetyScreen44 panel, high solubility, favorable metabolic stability, and even did not block CYP/P‐glycoprotein. In addition, NLX‐204 stimulated ERK 1/2 phosphorylation in the rat cortex and exhibited completely abolishing immobility at a dose of 2.5 mg kg −1 (p.o.)…”

Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile

“…In the case of 5-HT 1A receptors, an important advance was the discovery of a first highly selective biased agonist, NLX-101 (aka F15599, 1 ), which shows a marked preference for ERK1/2 phosphorylation versus other signaling pathways (Figure ). , 1 displayed a strikingly superior activity profile in a variety of electrophysiology, microdialysis, behavior, and brain imaging studies, as compared to older, canonical 5-HT 1A receptor agonists. − In particular, 1 exhibited highly promising properties in models of antidepressant and procognitive activity as well as in models of respiratory deficits in Rett syndrome, an orphan disorder. , The discovery of 1 therefore opened the way for drug discovery of novel, selective biased agonists that target 5-HT 1A receptors in specific brain areas that control CNS functions and that constitute, potentially, more efficacious and safer pharmacotherapeutics.…”