123456Duan 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
123456Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, etal. (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, etal. (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].
