Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT_1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile

Abstract

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT 1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1 H -indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential “signaling fingerprints” that translated into distinct in vivo profiles. In vitro , 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo , it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo , a component of “serotonergic syndrome”. Both compounds showed promising developability properties. The presented 5-HT 1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.

Serotonin Receptor and Transporter Endocytosis Is an Important Factor in the Cellular Basis of Depression and Anxiety

“…A recent study by Sniecikowska et al ( 2020 ) has identified new 5-HT 1A -specific antidepressant compounds, highlighting the importance of endosomal signaling through 5-HT receptors in regards to developing novel antidepressants. “Compound 44” induced potent ERK activation, while inducing β-arrestin recruitment to 5-HT 1A and cAMP production at a level comparable to serotonin.…”

“…“Compound 56” potently induced β-arrestin recruitment compared to serotonin or compound 44, and increased ERK activation and cAMP production to a much greater extent than compound 44. Compound 56 also acted as an antidepressant in mice, but also led to serotonin syndrome (i.e., serotonin overdose) (Sniecikowska et al, 2020 ). Similar to cAMP, ERK can be activated at the plasma membrane or intracellular compartments by either G-proteins or β-arrestins (Eishingdrelo, 2013 ).…”

“…Similar to cAMP, ERK can be activated at the plasma membrane or intracellular compartments by either G-proteins or β-arrestins (Eishingdrelo, 2013 ). The potent β-arrestin recruitment and signaling outcomes induced by compound 56 compared to compound 44 and serotonin (Sniecikowska et al, 2020 ), highlights the likelihood that endosomal signaling is an important component of the 5-HT 1A receptor response.…”

Membrane protein production and formulation for drug discovery

“…This type of assay was originally applied to discover biased ligands that favor G-protein signaling for opioid receptors [61], ultimately resulting in the first drug designed as a biased agonist, oliceridine (FDA-approved in August 2020), which has reduced adverse effects compared with morphine. Similar assays have facilitated the discovery of biased ligands for the nociception opioid peptide (NOP) [62] and serotonin HT1A [63] receptors. Although ion channel/transporter interactions with function-modulating proteins are not as well characterized compared with GPCRs, there is great potential to apply similar assays to those systems, as in a recent example where a peptide disrupting the Na v 1.6/fibroblast growth factor interaction was discovered [64].…”

Novel and atypical pathways for serotonin signaling

“…As for many GPCRs, biased ligands acting on 5-HT receptors are actively searched in order to obtain more selective drugs with fewer side effects 62 – 65 . Agonists acting at 5-HT 2A receptors represent one of the most striking illustrations of functional selectivity 66 , 67 .…”