Fig. 4: β-Arrestin-biased 5-HT2A agonists lack psychedelic potential.
From: Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential
A 25N-NBOMe (4) induces the head-twitch response (HTR) (W5,19.46 = 84.56, p < 0.0001). B 25N-N1-Nap (16) does not induce the HTR (F5,26 = 1.39, p = 0.2618). C 25N-NBPh (17) does not induce the HTR (F4,18 = 0.89, p = 0.4903). D 25N-NB-2-OH-3-Me (18) does not induce the HTR (F2,25 = 0.55, p = 0.7377). E Illustration showing the procedures used to confirm that compounds tested in panels F–H are brain penetrant and capable of engaging 5-HT2A receptors in the CNS of mice. Mice were pretreated with vehicle or drug, ( ± )-DOI (1 mg/kg IP) was injected 10 minutes later, and then HTR activity was assessed for 20 minutes. F Pretreatment with 25N-N1-Nap (16) blocks the HTR induced by (±)-DOI (F3,16 = 68.43, p < 0.0001). G Pretreatment with 25N-NBPh (17) blocks the HTR induced by (±)-DOI (W3,14.64 = 144.6, p < 0.0001). H Pretreatment with 25N-NB-2-OH-3-Me (18) blocks the HTR induced by (±)-DOI (F3,16 = 18.39, p < 0.0001). P values are provided if there were significant differences between groups (Tukey’s test or Dunnett’s T3 test). HTR counts from individual male C57BL/6 J mice as well as group means are shown. Drug doses are presented as mg/kg. I 5-HT2A receptor Gq-mediated calcium flux activity comparing 5-HT (open circles) antagonist activity for 25N-N1-Nap (16) (red), 25N-NB-2-OH-3-Me (18) to M100,907 (black circles). Data represent the mean and SEM from three independent experiments. Source data are provided as a Source Data file.
