Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct 8;63(19):10946-10971.
doi: 10.1021/acs.jmedchem.0c00814. Epub 2020 Sep 23.

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

Joanna Sniecikowska  1 , Monika Gluch-Lutwin  1 , Adam Bucki  1 , Anna Więckowska  1 , Agata Siwek  1 , Magdalena Jastrzebska-Wiesek  1 , Anna Partyka  1 , Daria Wilczyńska  1 , Karolina Pytka  1 , Gniewomir Latacz  1 , Katarzyna Przejczowska-Pomierny  1 , Elżbieta Wyska  1 , Anna Wesołowska  1 , Maciej Pawłowski  1 , Adrian Newman-Tancredi  2 , Marcin Kolaczkowski  1
Affiliations

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

Joanna Sniecikowska et al. J Med Chem. .

Abstract

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A 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-(1H-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-HT1A 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.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing financial interest(s): A.N.-T. is an employee and a shareholder of Neurolixis.

Figures

Figure 1
Figure 1
Selective 5-HT1A receptor-biased agonists.
Chart 1
Chart 1. Graphical Visualization of Selectivity Profiles of Compounds 3, 44, and 56a
Scheme 1
Scheme 1. Synthesis of 1-(1-Benzoyl-4-fluoropiperidin-4-yl)methanamine Derivatives
Reagents and conditions: (i) DABCO, NaCNBH3, FeSO4 × 7H2O, molecular sieves, MeOH, r.t., 36–72 h, yield: 18–82%; (ii) 1.0 M HCl in EtOAc, r.t., 24 h, yield: 48%; (iii) CH3COOH, NaCNBH3, 15 °C—15 min, then r.t—1 h, yield: 67%. X = F or Cl.
Scheme 2
Scheme 2. Synthesis of the Amine Intermediates (6–26)
Reagents and conditions: (i) for compounds II 24–26, tert-butyl-2-hydroxyethyl carbamate or 2-(2-hydroxyethyl)isoindoline-1,3-dion, PPh3, DIAD, THF, 0 °C then r.t, 24 h, and 50 °C, 24 h; (ii) 1,2-dibromoethane, K2CO3, acetone, 40–80 °C, 24–72 h; (iii) for compounds II 6–16, 18–23, potassium phthalimide, 18-crown-6 ether, DMF, 50 °C, 3 h; (iv) NaH, CH3I, THF, 0 °C, 30 min, then r.t, 1 h; for compound II 17 (iv) and then (iii); (v) for compounds 6–23, 25, 26, 40% MeNH2(aq), 10% NaOH, 50 °C, 2 h, then r.t., 1 h. (vi) For compound 24, 1.0 M HCl in EtOAc, r.t, 24 h; R1 = phthalimide or tert-butyl carbamate.
Figure 2
Figure 2
Predicted binding mode of the methoxy derivatives, that is, compound 36 (light teal) together with 38 (pink) (A) and compound 40 (gray) (B) in the site of the serotonin 5-HT1A receptor. Amino acid residues engaged in ligand binding (within 4 Å from the ligand atoms) are displayed as sticks, whereas crucial residues, for example, forming H-bonds (dotted yellow lines), π–π/CH−π stacking (dotted cyan lines), and cation−π interactions (dotted green line) are represented as thick sticks. ECL2 residues were hidden for clarity; ECL—extracellular loop. The homology model of the 5-HT1A receptor is based on the crystal structure of the 5-HT1B receptor (PDB ID: 4IAR).
Figure 3
Figure 3
Predicted binding mode of the fluoro derivatives, that is, compound 28 (yellow) together with 29 (pink) and 31 (green) in the site of the serotonin 5-HT1A receptor. Amino acid residues engaged in ligand binding (within 4 Å from the ligand atoms) are displayed as sticks, whereas crucial residues, for example, forming H-bonds (dotted yellow lines), π–π/CH−π stacking (dotted cyan lines), and cation−π interactions (dotted green line) are represented as thick sticks. ECL2 residues were hidden for clarity; ECL—extracellular loop. The homology model of the 5-HT1A receptor is based on the crystal structure of the 5-HT1B receptor (PDB ID: 4IAR).
Figure 4
Figure 4
Predicted binding mode of compound 56 (with HBD in meta position) in the site of the serotonin 5-HT1A receptor. Amino acid residues engaged in ligand binding (within 4 Å from the ligand atoms) are displayed as sticks, whereas crucial residues, for example, forming H-bonds (dotted yellow lines), π–π/CH−π stacking (dotted cyan lines), and cation−π interactions (dotted green line) are represented as thick sticks. ECL2 residues were hidden for clarity; ECL—extracellular loop. The homology model of the 5-HT1A receptor is based on the crystal structure of the 5-HT1B receptor (PDB ID: 4IAR).
Figure 5
Figure 5
Changes in LLE in relation to unsubstituted lead structure 3 due to substitution at the phenyl ring.
Figure 6
Figure 6
“Signaling fingerprints” for reference compounds (bar height—normalized ligand potency in log scale, bar color—ligand efficacy, as percent Emax).
Figure 7
Figure 7
“Signaling fingerprints” for the novel compounds (bar height—normalized ligand potency in log scale, bar color—ligand efficacy, as percent Emax). The signaling fingerprints for 2 and 3 are shown for comparison with our previous work.
Chart 2
Chart 2. Differential Profiles in the FST (in Blue) and LLR (in Red) of Compounds 44 (A) and 56 (B), the 5-HT1AR-Biased Agonists with Contrasting Functional Selectivity Signaling Fingerprints (Preferential for pERK1/2 and β-Arrestin, Respectively)a
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Pazos A.; Palacios J. M. Quantitative Autoradiographic Mapping of Serotonin Receptors in the Rat Brain. I. Serotonin-1 Receptors. Brain Res. 1985, 346, 205–230. 10.1016/0006-8993(85)90856-x. - DOI - PubMed
    1. Fargin A.; Raymond J. R.; Lohse M. J.; Kobilka B. K.; Caron M. G.; Lefkowitz R. J. The Genomic Clone G-21 Which Resembles a β-Adrenergic Receptor Sequence Encodes the 5-HT 1A Receptor. Nature 1988, 335, 358–360. 10.1038/335358a0. - DOI - PubMed
    1. Peroutka S. J. Selective Interaction of Novel Anxiolytics with 5-Hydroxytryptamine1A Receptors. Biol. Psychiatry 1985, 20, 971–979. 10.1016/0006-3223(85)90194-5. - DOI - PubMed
    1. Jordan S.; Koprivica V.; Chen R.; Tottori K.; Kikuchi T.; Altar C. A. The Antipsychotic Aripiprazole Is a Potent, Partial Agonist at the Human 5-HT1A Receptor. Eur. J. Pharmacol. 2002, 441, 137–140. 10.1016/s0014-2999(02)01532-7. - DOI - PubMed
    1. Adell A. Lu-AA21004, a Multimodal Serotonergic Agent, for the Potential Treatment of Depression and Anxiety. IDrugs 2010, 12, 900–910. - PubMed

Publication types

LinkOut - more resources