(R)-69

Chemical compound vanc 6 (R)-69 (R)-69.svg skin-invert-image 175px Non-hallucinogenic Serotonin 5-HT2A receptor agonist correct CAS 2765652-48-8 129875387 164513426 L3MT297ZZJ 5399968 3IQ R-69; 3IQ 3-[(5R)-5-methyl-1,2,5,6-tetrahydropyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine 13 15 3 C[C@@H]1C=C(CNC1)c1c[NH]c2ncccc12 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 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. 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 252598838 2022Natur.610..582K It has a 5-HT2A Ki of 680 nM and an EC50 of 41 nM. (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. Peeters J, De Bundel D, Vanommeslaeghe K Molecular dynamics study of differential effects of serotonin-2A-receptor (5-HT2AR) modulators PLOS Computational Biology 21 9 e1013000 September 2025 40901933 12443254 10.1371/journal.pcbi.1013000 free 2025PLSCB..21E3000P In animal studies it produces antidepressant-like activity but without producing the head-twitch response associated with psychedelic effects. 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. A number of related derivatives have also been developed. Li R, Yan H, Chen Y, Liu Y, Tang L, Yu J, Liu J, Wang H, Wang S, Cheng J Structure-Guided Design of Novel 5-HT2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects Journal of Medicinal Chemistry October 2025 41087124 10.1021/acs.jmedchem.5c02045 acs.jmedchem.5c02045 Jastrzębski MK, Wójcik P, Grudzińska A, Andreozzi G, Vetrò T, Asim A, Mudgal A, Czapiński J, Wróbel TM, Bartuzi D, Targowska-Duda KM, Kaczor AA Biased signaling via serotonin 5-HT2A receptor: From structural aspects to in vitro and in vivo pharmacology Acta Pharmaceutica Sinica. B 15 9 4438–4455 September 2025 41049744 10.1016/j.apsb.2025.07.002 free 12491688 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)-70 References External links - (R)-69 - Isomer Design Category:Biased ligands Category:Designer drugs Category:Non-hallucinogenic 5-HT2A receptor agonists Category:Tetrahydropyridinylpyrrolopyridines