All test compounds exhibited agonist properties with a range of EC50 values.
The study focused on the activation of the serotonin 2A receptor by various 4-position-substituted phenylalkylamines.
, or preferential activation of specific signaling pathways, was investigated in relation to β-arrestin2 and miniGα recruitment.
A correlation was found between the lipophilicity of 2C-X phenethylamines and their efficacy, particularly stronger in the miniGα assay.
Molecular docking suggested that the 4-substituent of 2C-X analogues may fit into a hydrophobic pocket in the receptor, influencing their activity.
The inclusion of serotonin as a reference agonist provided insights into both 'benchmark bias' relative to LSD and 'physiology bias' relative to serotonin.
Simplified
Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HTagonists remain elusive. One of the proposed hypotheses is the occurrence of , 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-benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGαto the 5-HT, allowing us to assess structure-activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both ECandvalues. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGα- 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-HTmay 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). 2A2A q2A50max q2A N E
Key numbers
12.3 nM
Potency Comparison
Potency of LSD as a reference agonist in β-arrestin2 recruitment assay.
191%
Efficacy of DOT
Efficacy of DOT (α-methyl derivative) in miniGα recruitment assay.
115%
Efficacy of Serotonin
Efficacy of serotonin in β-arrestin2 recruitment assay.
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