(R)-70

Chemical compound vanc 6 (R)-70 R-70.svg skin-invert-image 175px Non-hallucinogenic Serotonin 5-HT2A receptor agonist None 170328782 138533824 R-70 3-[(3R)-1,3-dimethyl-3,6-dihydro-2H-pyridin-5-yl]-1H-pyrrolo[2,3-b]pyridine 14 17 3 C[C@H]1CN(CC(=C1)C2=CNC3=C2C=CC=N3)C 1S/C14H17N3/c1-10-6-11(9-17(2)8-10)13-7-16-14-12(13)4-3-5-15-14/h3-7,10H,8-9H2,1-2H3,(H,15,16)/t10-/m1/s1 BVUHRQDBEWGRFX-SNVBAGLBSA-N (R)-70, or R-70, is a non-hallucinogenic selective serotonin 5-HT2 receptor moderate-efficacy partial agonist of the tetrahydropyridinylpyrrolopyridine family related to the psychedelic tryptamines. Duan W, Cao D, Wang S, Cheng J Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews 124 1 124–163 January 2024 38033123 10.1021/acs.chemrev.3c00375 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 Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, Kweon OS, Che T, McCorvy JD, Kamber DN, Phelan JP, Martins LC, Pogorelov VM, DiBerto JF, Slocum ST, Huang XP, Kumar JM, Robertson MJ, Panova O, Seven AB, Wetsel AQ, Wetsel WC, Irwin JJ, Skiniotis G, Shoichet BK, Roth BL, Ellman JA Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity Nature 610 7932 582–591 October 2022 36171289 9996387 10.1038/s41586-022-05258-z 2022Natur.610..582K 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, Kostenis E, Hsu LM, Shih YI, Roth BL, Herman MA Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation Translational Psychiatry 15 1 381 October 2025 41052972 12501219 10.1038/s41398-025-03611-0 free 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]. It shows preference for activation of the serotonin 5-HT2A receptor of about 6.4-fold relative to the serotonin 5-HT2B receptor and of about 30-fold relative to the serotonin 5-HT2C receptor. The drug is a biased agonist of the serotonin 5-HT2A receptor, activating Gq protein signaling more readily than β-arrestin2 signaling. It did not significantly produce the head-twitch response in mice, but did produce antidepressant-like effects. (R)-70, along with its close analogue (R)-69, was first described in the scientific literature by Bryan L. Roth and colleagues in 2022. It was identified via an ultra-large-scale docking campaign for the serotonin 5-HT2A receptor. See also Tetrahydropyridinylpyrrolopyridine Substituted tryptamine § Related compounds Cyclized tryptamine List of miscellaneous 5-HT2A receptor agonists Non-hallucinogenic 5-HT2A receptor agonist RU-24969 RU-28253 NEtPhOH-THPI SN-22 VU6067416 Z3517967757 (R)-69 References External links - (R)-70 - Isomer Design Category:Biased ligands Category:Methyl compounds Category:Non-hallucinogenic 5-HT2A receptor agonists Category:Tetrahydropyridinylpyrrolopyridines