Pyridopyrroloquinoxaline

Class of chemical compounds From Wikipedia, the free encyclopedia

A substituted pyridopyrroloquinoxaline, or more specifically a substituted octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline, also known as a substituted heterocycle fused γ-carboline, is a further-cyclized and substituted tetracyclic derivative of the tricyclic alkaloid γ-carboline as well as an analogue of the atypical antipsychotic lumateperone.^[1]^[2]^[3]^[4]^[5] They can additionally be thought of as analogues of cyclized tryptamines like the β-carbolines or harmala alkaloids such as harmaline, but are not technically tryptamines themselves.

Pyridopyrroloquinoxalines are notable for their varying interactions with the serotonin 5-HT_2A receptor as well as with other monoamine receptors.^[1]^[6] Lumateperone and deulumateperone are serotonin 5-HT_2A receptor antagonists with antipsychotic properties, IHCH-7113 is a putatively psychedelic serotonin 5-HT_2A receptor full agonist with a robust head-twitch response in rodents, and IHCH-7086, IHCH-7079, and ITI-1549 are putatively non-hallucinogenic β-arrestin-biased serotonin 5-HT_2A receptor partial agonists with psychoplastogenic and/or antidepressant-like effects in preclinical studies.^[7]^[1]^[8]^[9]^[10]^[11] The broad receptor interactions of some of these compounds have been studied.^[6]^[1]

Pyridopyrroloquinoxalines with serotonin 5-HT_2A receptor agonistic activity such as IHCH-7113 and IHCH-7086 were first described in the scientific literature by Dongmei Cao and colleagues by 2022.^[1] As of 2025, ITI-1549 is under development by Intra-Cellular Therapies for the treatment of mood and other psychiatric disorders.^[11]

List of pyridopyrroloquinoxalines

More information Structure, Name ...

Structure	Name	Chemical name
	IHCH-7113	(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline
	IHCH-7079	(6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-8-[2-(2-methoxyphenyl)ethyl]-3-methyl-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline
	IHCH-7086	(6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-8-[3-(2-methoxyphenyl)propyl]-3-methyl-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline
	Lumateperone (ITI-007)	1-(4-fluorophenyl)-4-(3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-butanone
	Deulumateperone (ITI-1284)	1-(4-fluorophenyl)-4-[(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-(2-2H)hexahydro(2-2H)-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl]butan-1-one
	ITI-1549	(6b'R,10a'S)-8'-[2-(1,2-benzoxazol-3-yl)ethyl]-2',3',6b',9',10',10a'-hexahydro-3'-methylspiro[cyclopropane-1,2'-[1H,7H]pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline]

Other known pyridopyrroloquinoxalines include IHCH-7081, IHCH-7087, IHCH-7088, IHCH-7089, IHCH-7112, and IHCH-7120.^[1]

Related compounds

More information Structure, Name ...

Structure	Name	Chemical name
	2MePI	2-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indole
	Tiflucarbine	9-ethyl-4-fluoro-1-methyl-7,8,9,10-tetrahydro-6H-pyrido[4,3-b]thieno[3,2-e]indole
	IHCH-8134	(6bR,10aS)-8-(3-(2-methoxyphenyl)propyl)-1,2,6b,7,8,9,10,10a-octahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole

References

[1]
Cao 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. PMID 35084960.
[2]
"Pyridopyrroloquinoxaline compounds, their compositions and uses in therapy". Google Patents. 20 July 2018. Retrieved 29 July 2025.
[3]
"Lumateperone and derivatives thereof for modulating the nervous system". Google Patents. 16 February 2024. Retrieved 29 July 2025.
[4]
"A pyridopyrroloquinoxaline compound and its medical use". Google Patents. 20 December 2019. Retrieved 29 July 2025.
[5]
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. PMID 30103193.
[6]
Sharp T, Ippolito A (May 2025). "Neuropsychopharmacology of hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists". Br J Pharmacol bph.70050. doi:10.1111/bph.70050. PMID 40405723.
[7]
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. 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 [...]
[8]
Yin YN, Gao TM (January 2023). "Non-hallucinogenic Psychedelic Analog Design: A Promising Direction for Depression Treatment". Neurosci Bull. 39 (1): 170–172. doi:10.1007/s12264-022-00933-7. PMC 9849505. PMID 35927548.
[9]
Ippolito A, Vasudevan S, Hurley S, Gilmour G, Westhorpe F, Churchill G, Sharp T (June 2025). "Evidence that 5-HT2A receptor signalling efficacy and not biased agonism differentiates serotonergic psychedelic from non-psychedelic drugs". Br J Pharmacol bph.70109. doi:10.1111/bph.70109. PMID 40545270.
[10]
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. PMC 12226698. PMID 38743110. 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).
[11]
Dutheil, Sophie; Lehmann, Vanessa E.; Awadallah, Nora; John, Neelu; Zhang, Lei; Yao, Wei; Li, Peng; Snyder, Gretchen; Davis, Robert (2025). "319. Discovery and Development of ITI-1549: A Novel Serotonin 5-HT2A Agonist, Non-Hallucinogenic Neuroplastogen, for the Treatment of Neuropsychiatric Disorders". Biological Psychiatry. 97 (9): S227. doi:10.1016/j.biopsych.2025.02.557. Retrieved 29 July 2025.

Pyridopyrroloquinoxaline

List of pyridopyrroloquinoxalines

Related compounds

See also

References

Related Articles