(R)-69

Last updated
(R)-69
R69 structure.png
Clinical data
Other namesR-69; 3IQ
Drug class Non-hallucinogenic Serotonin 5-HT2A receptor agonist
Identifiers
  • 3-[(5R)-5-methyl-1,2,5,6-tetrahydropyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C13H15N3
Molar mass 213.284 g·mol−1
3D model (JSmol)
  • C[C@@H]1C=C(CNC1)c1c[NH]c2ncccc12
  • InChI=1S/C13H15N3/c1-9-5-10(7-14-6-9)12-8-16-13-11(12)3-2-4-15-13/h2-5,8-9,14H,6-7H2,1H3,(H,15,16)/t9-/m1/s1
  • Key:HNDPIXZRQWKEFZ-SECBINFHSA-N

(R)-69 (3IQ) is a drug of the tetrahydropyridinylpyrrolopyridine family related to the psychedelic tryptamines which acts as a 5-HT2A receptor agonist, with 4.6-fold selectivity over 5-HT2B and 49-fold selectivity over 5-HT2C. [1] [2] It has a 5-HT2A Ki of 680 nM and an EC50 of 41 nM. [1] [2] (R)-69 is a biased agonist selective for activation of the Gq coupled signalling pathway, with much weaker activation of the β-arrestin 2 coupled pathway. [1] [2] In animal studies it produces antidepressant-like activity but without producing the head-twitch response associated with psychedelic effects. [1] [2] The drug was identified along with its close analogue (R)-70 via an ultra-large-scale docking campaign against the serotonin 5-HT2A receptor and was first described by Bryan L. Roth and colleagues in 2022. [1] [2]

Contents

See also

References

  1. 1 2 3 4 5 Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chem Rev. 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. 1 2 3 4 5 Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, et al. (September 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. PMC   9996387 . PMID   36171289. S2CID   252598838.



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