Fig. 2: Rational design of a 5-HT2A-selective agonist template.
From: Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential
A N-Benzylation of 25N (1) to 25N-NB (2) leads to reduced 5-HT2B receptor efficacy, as measured by Gq dissociation by BRET. Data represent the mean and SEM from three independent experiments performed at 37 °C with 60-minute compound incubation. B Role of N-benzyl ring electrostatics in 5-HT2A receptor potency leading to development of 25N-NB-2-OH-3-Me (18) using QSAR correlation between 5-HT2A receptor pKi and Hammett σ constant values (Pearson’s R = −0.8887, R2 = 0.7897, 2-tailed p < 0.0001, N = 15). C The relationship between steric bulk and 5-HT2A/2C receptor selectivity is shown for the halogen series, leading to the identification of the 5-HT2A receptor-selective agonist 25N-NBI (10) (left). Also shown is a 5-HT2A/2C receptor selectivity heatmap comparing the 25N halogen series to 25CN-NBOH (right). D Comparison of 5-HT2A receptor (green) 5-HT2B receptor (red) and 5-HT2C receptor (purple) Gq dissociation activities for 25N-NBI (10) (left) and 25CN-NBOH (right). Data represent mean and SEM from three independent experiments, which were performed at 37 °C with 60-minute compound incubation. E 5-HT2A receptor Gq dissociation and β-arrestin2 BRET concentration response curves for 25N-NBOH (3, top) and 25N-NB-2-OH-3-Me (18, bottom) showing addition of a 3-methyl group leads to reduced Gq-efficacy. Data represent mean and SEM from three independent experiments, which were performed at 37 °C with 60-minute compound incubation. F 25N-NBI (10) induced fit docking (IFD) with orthosteric site residue side chains displayed. The window shows a zoom-in view illustrating key ligand-residue interactions within the orthosteric site and illustrating the close proximity of the 2’- and 3’-positions to TM6 and TM7, which are known to influence ligand bias. G Summary of structure-activity relationships (SAR) for the 25N series encompassing key effects on electrostatics, 5-HT2A receptor selectivity, and reduced Gq EMAX. Source data are provided as a Source Data file.
