TY - JOUR
T1 - Structure–Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists
AU - Pottie, Eline
AU - B. M. Poulie, Christian
AU - Simon, Icaro Ariel
AU - Harpsøe, Kasper
AU - d'Andrea, Laura
AU - komarov, igor
AU - Gloriam, David
AU - Jensen, Anders
AU - L. Kristensen, Jesper
AU - Stove, Christophe
PY - 2023/8/2
Y1 - 2023/8/2
N2 - 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 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 and Emax 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).
AB - 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 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 and Emax 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).
KW - 5-HT2A
KW - biased agonism
KW - in vitro pharmacology
KW - miniGα
KW - psychedelics
KW - β-arrestin
UR - http://www.scopus.com/inward/record.url?scp=85166387661&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.3c00267
DO - 10.1021/acschemneuro.3c00267
M3 - Journal article
C2 - 37474114
SN - 1948-7193
VL - 14
SP - 2727
EP - 2742
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 15
ER -