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(R)-69

From Wikipedia, the free encyclopedia
Chemical compound

Pharmaceutical compound
(R)-69
Clinical data
Other namesR-69; 3IQ
Drug classNon-hallucinogenicSerotonin5-HT2A receptoragonist
Identifiers
  • 3-[(5R)-5-methyl-1,2,5,6-tetrahydropyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine
CAS Number
PubChemCID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC13H15N3
Molar mass213.284 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 adrug of thetetrahydropyridinylpyrrolopyridine family related to thepsychedelictryptamines which acts as a5-HT2A receptoragonist, with 4.6-foldselectivity over5-HT2B and 49-fold selectivity over5-HT2C.[1][2] It has a 5-HT2A Ki of 680 nM and an EC50 of 41 nM.[1][2] (R)-69 is abiased agonist selective for activation of theGq coupled signalling pathway, with much weaker activation of theβ-arrestin 2 coupled pathway.[1][2][3] In animal studies it producesantidepressant-like activity but without producing thehead-twitch response associated withpsychedelic effects.[1][2] The drug was identified along with its closeanalogue(R)-70 via anultra-large-scale docking campaign against the serotonin 5-HT2A receptor and was first described byBryan L. Roth and colleagues in 2022.[1][2] A number of related derivatives have also been developed.[4][5]

See also

[edit]

References

[edit]
  1. ^abcdeDuan 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.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. ^abcdeKaplan 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.PMC 9996387.PMID 36171289.S2CID 252598838.
  3. ^Peeters J, De Bundel D, Vanommeslaeghe K (September 2025)."Molecular dynamics study of differential effects of serotonin-2A-receptor (5-HT2AR) modulators".PLOS Computational Biology.21 (9) e1013000.Bibcode:2025PLSCB..21E3000P.doi:10.1371/journal.pcbi.1013000.PMC 12443254.PMID 40901933.
  4. ^Li R, Yan H, Chen Y, Liu Y, Tang L, Yu J, et al. (October 2025). "Structure-Guided Design of Novel 5-HT2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects".Journal of Medicinal Chemistry acs.jmedchem.5c02045.doi:10.1021/acs.jmedchem.5c02045.PMID 41087124.
  5. ^Jastrzębski MK, Wójcik P, Grudzińska A, Andreozzi G, Vetrò T, Asim A, et al. (September 2025)."Biased signalingvia serotonin 5-HT2A receptor: From structural aspects toin vitro andin vivo pharmacology".Acta Pharmaceutica Sinica. B.15 (9):4438–4455.doi:10.1016/j.apsb.2025.07.002.PMC 12491688.PMID 41049744.

External links

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5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT3–7
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
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