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Structure-activity assessment and in-depth analysis of biased agonism in a set of phenylalkylamine 5‑HT2A receptor agonists

Eline Pottie (UGent) , Christian B. M. Poulie, Icaro A. Simon, Kasper Harpsøe, Laura D'Andrea, Igor V. Komarov, David E. Gloriam, Anders A. Jensen, Jesper L. Kristensen and Christophe Stove (UGent)
(2023) ACS CHEMICAL NEUROSCIENCE. 14(15). p.2727-2742
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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 (and N-benzyl-derived) phenylalkylamines to induce recruitment of beta-arrestin2 (beta arr2) or miniG alpha(q) 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 and E-max values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniG alpha(q)- than in the beta arr2-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
SEROTONIN 5-HYDROXYTRYPTAMINE(2A) RECEPTOR, HALLUCINOGENIC PHENETHYLAMINE, ACCURATE DOCKING, PHOSPHOLIPASE-C, BINDING, SITE, ANALOGS, GLIDE, LIPOPHILICITY, PHARMACOLOGY, 5-HT2A, biased agonism, psychedelics, in vitro pharmacology, beta-arrestin, miniG alpha(q)

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Citation

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MLA
Pottie, Eline, et al. “Structure-Activity Assessment and in-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5‑HT2A Receptor Agonists.” ACS CHEMICAL NEUROSCIENCE, vol. 14, no. 15, 2023, pp. 2727–42, doi:10.1021/acschemneuro.3c00267.
APA
Pottie, E., Poulie, C. B. M., Simon, I. A., Harpsøe, K., D’Andrea, L., Komarov, I. V., … Stove, C. (2023). Structure-activity assessment and in-depth analysis of biased agonism in a set of phenylalkylamine 5‑HT2A receptor agonists. ACS CHEMICAL NEUROSCIENCE, 14(15), 2727–2742. https://doi.org/10.1021/acschemneuro.3c00267
Chicago author-date
Pottie, Eline, Christian B. M. Poulie, Icaro A. Simon, Kasper Harpsøe, Laura D’Andrea, Igor V. Komarov, David E. Gloriam, Anders A. Jensen, Jesper L. Kristensen, and Christophe Stove. 2023. “Structure-Activity Assessment and in-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5‑HT2A Receptor Agonists.” ACS CHEMICAL NEUROSCIENCE 14 (15): 2727–42. https://doi.org/10.1021/acschemneuro.3c00267.
Chicago author-date (all authors)
Pottie, Eline, Christian B. M. Poulie, Icaro A. Simon, Kasper Harpsøe, Laura D’Andrea, Igor V. Komarov, David E. Gloriam, Anders A. Jensen, Jesper L. Kristensen, and Christophe Stove. 2023. “Structure-Activity Assessment and in-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5‑HT2A Receptor Agonists.” ACS CHEMICAL NEUROSCIENCE 14 (15): 2727–2742. doi:10.1021/acschemneuro.3c00267.
Vancouver
1.
Pottie E, Poulie CBM, Simon IA, Harpsøe K, D’Andrea L, Komarov IV, et al. Structure-activity assessment and in-depth analysis of biased agonism in a set of phenylalkylamine 5‑HT2A receptor agonists. ACS CHEMICAL NEUROSCIENCE. 2023;14(15):2727–42.
IEEE
[1]
E. Pottie et al., “Structure-activity assessment and in-depth analysis of biased agonism in a set of phenylalkylamine 5‑HT2A receptor agonists,” ACS CHEMICAL NEUROSCIENCE, vol. 14, no. 15, pp. 2727–2742, 2023.
@article{01HKSP4M4EAJW6K41YXJ05T517,
  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 (and N-benzyl-derived) phenylalkylamines to induce recruitment of beta-arrestin2 (beta arr2) or miniG alpha(q) 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 and E-max values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniG alpha(q)- than in the beta arr2-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).}},
  author       = {{Pottie, Eline and Poulie, Christian B. M. and  Simon, Icaro A. and Harpsøe, Kasper and  D'Andrea, Laura and  Komarov, Igor V. and  Gloriam, David E. and  Jensen, Anders A. and  Kristensen, Jesper L. and Stove, Christophe}},
  issn         = {{1948-7193}},
  journal      = {{ACS CHEMICAL NEUROSCIENCE}},
  keywords     = {{SEROTONIN 5-HYDROXYTRYPTAMINE(2A) RECEPTOR,HALLUCINOGENIC PHENETHYLAMINE,ACCURATE DOCKING,PHOSPHOLIPASE-C,BINDING,SITE,ANALOGS,GLIDE,LIPOPHILICITY,PHARMACOLOGY,5-HT2A,biased agonism,psychedelics,in vitro pharmacology,beta-arrestin,miniG alpha(q)}},
  language     = {{eng}},
  number       = {{15}},
  pages        = {{2727--2742}},
  title        = {{Structure-activity assessment and in-depth analysis of biased agonism in a set of phenylalkylamine 5‑HT2A receptor agonists}},
  url          = {{http://doi.org/10.1021/acschemneuro.3c00267}},
  volume       = {{14}},
  year         = {{2023}},
}
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