Pyridopyrroloquinoxalines with serotonin 5-HT2A receptor agonistic activity such as IHCH-7113 and IHCH-7086 were first described in thescientific literature by Dongmei Cao and colleagues by 2022.[1] As of 2025, ITI-1549 is under development by Intra-Cellular Therapies for the treatment ofmood and otherpsychiatric disorders.[11]
^abcdefCao D, Yu J, Wang H, Luo Z, Liu X, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J, Wang S (January 2022). "Structure-based discovery of nonhallucinogenic psychedelic analogs".Science.375 (6579):403–411.Bibcode:2022Sci...375..403C.doi:10.1126/science.abl8615.PMID35084960.
^Dai J, Dan W, Zhang Y, Wang J (September 2018). "Recent developments on synthesis and biological activities of γ-carboline".Eur J Med Chem.157:447–461.doi:10.1016/j.ejmech.2018.08.015.PMID30103193.
^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.PMID38033123.Truncation of the tail group attached to the tetracyclic core of lumateperone resulted in compound IHCH-7113 (166, Figure 14C), which turned out to be a potent 5-HT2AR agonist (Gq BRET, EC50 = 58.9 nM (99.2%); β-arrestin2 BRET, EC50 = 44.7 nM (95.6%)). The introduction of a 2-methoxyphenyl tail bridged by either two or three CH2 groups led to compounds IHCH-7079 (167) and IHCH-7086 (168) (Figure 14C), respectively. Both compounds bind to the 5-HT2AR with high affinity (Ki = 16.98 and 12.59 nM, respectively; [3H]-LSD). In functional assays, compound IHCH-7079 showed a preference for β-arrestin2 recruitment (bias factor = 54.58). Compound IHCH-7086 behaved as a weak partial agonist in the βarrestin2 BRET assay (EC50 = 204.2 nM, Emax = 12.7%) but exhibited no Gq activation. Therefore, both compounds are β-arrestin-biased. Neither IHCH-7079 nor IHCH-7086 induced HTRs in mice at a dose of 10 mg/kg, but both compounds demonstrated significant antidepressant effects in acute stressand corticosterone-induced depression-like mouse models.60 Our results suggest that β-arrestin-biased 5-HT2AR partial agonists hold the potential as nonhallucinogenic psychedelic analogues for the development of novel antidepressant drugs. [...] Our research has identified β-arrestin-biased 5-HT2AR agonists, such as compounds IHCH-7079 and IHCH-7086,60 which exhibit varying degrees of β-arrestin-bias (Table 1). Notably, IHCH-7086 acts as a completely β-arrestin-biased 5-HT2AR agonist, with a high binding affinity at the receptor but no activation of the Gq pathway. We demonstrated that IHCH-7086 produces significant antidepressant effects in the absence of hallucinogenic effects in mouse behavioral models.60 [...]
^Atiq MA, Baker MR, Voort JL, Vargas MV, Choi DS (July 2025)."Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties".Psychopharmacology (Berl).242 (7):1481–1506.doi:10.1007/s00213-024-06599-5.PMC12226698.PMID38743110.What followed was the development of ß-arrestin-biased ligands ('IHCH-7079' and 'IHCH-7086') without detectable Gq activity. Upon testing for hallucinogenic activity, IHCH-7079 and IHCH-7086 failed to produce any HTR and were also found to abolish LSD-induced HTR. In vivo studies of antidepressant potential, as measured by the FST and tail suspension test (TST), revealed significantly attenuated acute-restraint stress-induced immobility with the two ligands, an efect that was eliminated by a selective 5-HT2AR antagonist (MDL100907).
