(R)-70

(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.^[1]^[2]^[3] It shows preference for activation of the serotonin 5-HT_2A receptor of about 6.4-fold relative to the serotonin 5-HT_2B receptor and of about 30-fold relative to the serotonin 5-HT_2C receptor.^[1]^[2] The drug is a biased agonist of the serotonin 5-HT_2A receptor, activating G_q protein signaling more readily than β-arrestin2 signaling.^[1]^[2] It did not significantly produce the head-twitch response in mice, but did produce antidepressant-like effects.^[1]^[2] (R)-70, along with its close analogue (R)-69, was first described in the scientific literature by Bryan L. Roth and colleagues in 2022.^[1]^[2] It was identified via an ultra-large-scale docking campaign for the serotonin 5-HT_2A receptor.^[1]^[2]

Other namesR-70

Drug classNon-hallucinogenic Serotonin 5-HT_2A receptor agonist

ATC code

None

PubChem CID

170328782

Quick facts Clinical data, Other names ...

(R)-70
Clinical data

Other names	R-70
Drug class	Non-hallucinogenic Serotonin 5-HT_2A receptor agonist
ATC code	None
Identifiers
IUPAC name 3-[(3R)-1,3-dimethyl-3,6-dihydro-2H-pyridin-5-yl]-1H-pyrrolo[2,3-b]pyridine
PubChem CID	170328782
Chemical and physical data
Formula	C₁₄H₁₇N₃
Molar mass	227.311 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C[C@H]1CN(CC(=C1)C2=CNC3=C2C=CC=N3)C
InChI InChI=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 Key:BVUHRQDBEWGRFX-SNVBAGLBSA-N

References

[1]
Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT_2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chemical Reviews. 124 (1): 124–163. doi:10.1021/acs.chemrev.3c00375. PMID 38033123. 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
[2]
Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, et al. (October 2022). "Bespoke library docking for 5-HT_2A receptor agonists with antidepressant activity". Nature. 610 (7932): 582–591. Bibcode:2022Natur.610..582K. doi:10.1038/s41586-022-05258-z. PMC 9996387. PMID 36171289. 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. [...]
[3]
Schmitz GP, Chiu YT, Foglesong ML, Magee SN, MacKinnon M, König GM, et al. (October 2025). "Psychedelic compounds directly excite 5-HT_2A layer V medial prefrontal cortex neurons through 5-HT_2A Gq activation". Translational Psychiatry. 15 (1) 381. doi:10.1038/s41398-025-03611-0. PMC 12501219. PMID 41052972. 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].

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