Movatterモバイル変換

[0]ホーム
URL:

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

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

American Chemical Society full text link American Chemical Society Free PMC article
Full text links

Actions

Share

.2023 Aug 2;14(15):2727-2742.
doi: 10.1021/acschemneuro.3c00267. Epub 2023 Jul 20.

Structure-Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists

Affiliations

Structure-Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists

Eline Pottie et al. ACS Chem Neurosci..

Abstract

Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT2A) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HT2A agonists remain elusive. One of the proposed hypotheses is the occurrence of biased agonism, defined as the preferential activation of certain signaling pathways over others. This study comparatively monitored the efficiency of a diverse panel of 4-position-substituted (andN-benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGαq to the 5-HT2A, allowing us to assess structure-activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both EC50 andEmax values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGαq- than in the βarr2-assay. Molecular docking suggested that accommodation of the 4-substituent of the 2C-X analogues in a hydrophobic pocket between transmembrane helices 4 and 5 of 5-HT2A may contribute to this differential effect. Aside from previously used standard conditions (lysergic acid diethylamide (LSD) as a reference agonist and a 2 h activation profile to assess a compound's activity), serotonin was included as a second reference agonist, and the compounds' activities were also assessed using the first 30 min of the activation profile. Under all assessed circumstances, the qualitative structure-activity relationships remained unchanged. Furthermore, the use of two reference agonists allowed for the estimation of both "benchmark bias" (relative to LSD) and "physiology bias" (relative to serotonin).

Keywords: 5-HT2A; biased agonism; in vitro pharmacology; miniGαq; psychedelics; β-arrestin.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing financial interest(s): D.E.G. is a part-time employee and warrant holder of Kvantify.

Figures

Figure 1
Figure 1
Schematic depiction of the structures of the phenylalkylamineanaloguesassessed in the present study, with phenethylamines (2C-X) highlightedin gray, phenylisopropylamines (DOX) highlighted in yellow, andN-benzylphenethylamines (25X-NB) highlighted in blue. Orangearrows denote the structural comparisons of compounds that only differin terms of their 4-position substituent, green arrows indicate thecomparisons of 2C-X analogues with the corresponding DOX analogues,and blue arrows indicate the comparison between 2C-X analogues andtheir N-benzyl-derived counterparts. The R2 and R3 substituents are consistent with Scheme 1.
Figure 2
Figure 2
(a–c) Predicted binding poses and ligand–receptorinteractions of selected 4-substituted phenethylamines at the 5-HT2A. The ligands are displayed as sticks, while the receptoris shown as gray lines and cartoon. Ligand–receptor interactionsare displayed as dashed lines and colored in green (aromatic, π–πstacking), yellow (hydrogen bond), and pink (salt-bridge). The receptorhydrophobic sub-pocket between TM4 and TM5 is shown as a surface andcolored according to the Eisenberg hydrophobicity scale, from highly hydrophilic (blue) to highly hydrophobic(yellow). (d) Linear correlation curve between the miniGαq (blue) and βarr2 (orange) recruitment assayEmax values and calculatedc log D values at pH 7.40.
Figure 3
Figure 3
Concentration–response curves for each of the compoundsin the βarr2 (orange) and miniGαq (blue) recruitmentassays at the 5-HT2A. Each point represents the mean ofthree independent experiments, each performed in duplicate ±SEM (standard error of the mean). Curves represent three parametric,nonlinear fits of normalized and pooled data for each concentrationtested, normalized with LSD as a reference agonist.
Figure 4
Figure 4
Visual representation of the bias factors (β) ±SEM(standard error of the mean), where ** stands forp < 0.01 in the nonparametric Kruskal–Wallis analysis ofsignificance with post hoc Dunn’s test. LSD is used as thereference agonist.
Figure 5
Figure 5
Qualitative bias plots, where each panel shows the centeredsecond-orderpolynomial fit of the activation values at equimolar concentrationsof the substance in the respective assays in red, and that of thereference agonist (in this case LSD) in black.
Figure 6
Figure 6
Visual representation of the differences in ranking orderof thesubstances’ efficacies in the βarr2 and miniGαq assay at the 5-HT2A. Thex-axisshows the relative ranking of the substance in the βarr2 assay,and the y-axis shows that in the miniGαq assay. Thesubstances that are on the right part of the “identity line”have a relative preference toward miniGαq recruitment,and the ones above the line toward βarr2 recruitment, with substancesbeing further away from the unity line having a larger differencein ranking order.
Scheme 1
Scheme 1. Synthesis of the Phenylalkylamines and Their CorrespondingN-Benzyl Analogues
Reaction conditions:(a) (i)aldehyde, EtOH, rt; (ii) NaBH4, EtOH, rt; (b) (i) phthalicanhydride, toluene, reflux; (ii) TiCl4, dichloromethylmethyl ether/4-chlorobutanoyl chloride, CH2Cl2, −10 to 0 °C; (iii) NaBH4, EtOH, rt; (iv)NaH, EtI, DMF, 0 °C to rt; (v) hydrazine (aq.), THF, rt; (c)HNO3 (70%), AcOH, 0 °C–rt. (d) (i) Br2, AcOH, rt; (ii) phthalic anhydride, toluene, reflux; (iii) Cu(I)CN,DMF, reflux; (iv) hydrazine (aq.), THF, rt.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Barnes N. M.; Ahern G. P.; Becamel C.; Bockaert J.; Camilleri M.; Chaumont-Dubel S.; Claeysen S.; Cunningham K. A.; Fone K. C.; Gershon M.; et al. International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function. Pharmacol. Rev. 2021, 73, 310–520. 10.1124/pr.118.015552. - DOI - PMC - PubMed
    1. Nichols D. E. Hallucinogens. Pharmacol. Ther. 2004, 101, 131–181. 10.1016/j.pharmthera.2003.11.002. - DOI - PubMed
    1. Glennon R. A.; Titeler M.; McKenney J. D. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 1984, 35, 2505–2511. 10.1016/0024-3205(84)90436-3. - DOI - PubMed
    1. Halberstadt A. L. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav. Brain Res. 2015, 277, 99–120. 10.1016/j.bbr.2014.07.016. - DOI - PMC - PubMed
    1. McClure-Begley T. D.; Roth B. L. The promises and perils of psychedelic pharmacology for psychiatry. Nat. Rev. Drug Discovery 2022, 21, 463–473. 10.1038/s41573-022-00421-7. - DOI - PubMed

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full text links
American Chemical Society full text link American Chemical Society Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp