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 - Poulie, Christian B. M.

AU - Simon, Icaro A.

AU - Harpsøe, Kasper

AU - D’Andrea, Laura

AU - Komarov, Igor V.

AU - Gloriam, David E.

AU - Jensen, Anders A.

AU - Kristensen, Jesper L.

AU - Stove, Christophe P.

PY - 2023

Y1 - 2023

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).

U2 - 10.1021/acschemneuro.3c00267

DO - 10.1021/acschemneuro.3c00267

M3 - Journal article

C2 - 37474114

VL - 14

SP - 2727

EP - 2742

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 15

ER -