^abcdefDuan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants".Chemical Reviews.124 (1):124–163.doi:10.1021/acs.chemrev.3c00375.PMID38033123.Very recently, the docking of a bespoke tetrahydropyridines (THPs) library combined with a structure-based optimization approach by Kaplan et al. led to the discovery of novel 5-HT2AR agonists with antidepressant activity in mouse models.202 The docking of a virtual library of 75 million THP compounds against the model of 5-HT2AR yielded 17 initial hits, among which 4 compounds showed low-micromolar activities at either 5-HT2AR or 5-HT2BR. Further modifications afforded [...] compounds (R)-69 (170) and (R)-70 (171) as agonists (Ki = 680 and 880 nM; EC50 = 41 nM (90.1%) and 110 nM (73.3%) in the calcium flux assay, respectively) (Figure 14D). Both compounds showed moderate binding selectivity against the 5-HT2BR and 5-HT2CR, and overall better selectivity profiles than those of classic psychedelic 5-HT2AR agonists. Interestingly, compounds (R)-69 and (R)-70 were pharmacologically profiled as G protein-biased 5-HT2AR agonists and were demonstrated as nonhallucinogenic in the HTR test and could block LSD-induced HTR effects. Very importantly, the compounds exhibited both acute and lasting (at least over 24 h) antidepressant effects in several mouse behavioral models.202
^abcdefKaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, et al. (October 2022)."Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity".Nature.610 (7932):582–591.Bibcode:2022Natur.610..582K.doi:10.1038/s41586-022-05258-z.PMC9996387.PMID36171289.Structure-based optimization led to 5-HT2AR agonists (R)-69 and (R)-70 with EC50s of 41 and 110 nM and unusual signaling kinetics differing from psychedelic 5-HT2AR agonists. Cryo-EM structural analysis confirmed the predicted binding mode to the 5-HT2AR. The favorable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioral assays. Intriguingly, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, while both had potent anti-depressant activity in mouse models and were equi-efficacious to anti-depressants like fluoxetine at as little as 1/40th the dose. [...]
^Schmitz GP, Chiu YT, Foglesong ML, Magee SN, MacKinnon M, König GM, et al. (October 2025)."Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation".Translational Psychiatry.15 (1) 381.doi:10.1038/s41398-025-03611-0.PMC12501219.PMID41052972.To examine whether these actions could be applied in drug discovery, we examined the effects of the novel nonhallucinogenic, therapeutic 5-HT2AR agonist R-70 [25]. R-70 (10 µM) significantly increased firing consistent with the effects of psilocin and NBOH-2C-CN (Figure S4A, B). These effects were also blocked by prior administration of the 5-HT2A-specific antagonist M100907 (Figure S4C–F). [...] Whether the hallucinogenic and therapeutic effects of psychedelics are dissociable is an area of growing interest, particularly in novel compound development [25–27]. We tested one novel compound, the Gαq-biased R-70 and found that it elicited similar effects to psilocin and NBOH-2C-CN, that were also blocked by 5-HT2A antagonism. This is especially interesting because R-70 exhibits therapeutic effects but is devoid of hallucinogenic actions in rodents [25]. LSD preferentially signals through βArr2 at the 5-HT2A receptor [11, 57] and LSD-elicited responses are significantly attenuated or absent in βArr2-KO mice [58].
