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Quipazine

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Quipazine
Clinical data
Other names2-(1-Piperazinyl)quinoline; 2-Piperazinoquinoline; 1-(2-Quinolinyl)piperazine; 2-QP
Routes of
administration		Oral[1]
Drug classNon-selective serotonin receptor agonist; Serotonin reuptake inhibitor; Emetic; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Identifiers
  • 2-piperazin-1-ylquinoline
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.885 Edit this at Wikidata
Chemical and physical data
FormulaC13H15N3
Molar mass213.284 g·mol−1
3D model (JSmol)
  • C1CN(CCN1)C2=NC3=CC=CC=C3C=C2
  • InChI=1S/C13H15N3/c1-2-4-12-11(3-1)5-6-13(15-12)16-9-7-14-8-10-16/h1-6,14H,7-10H2 ☒N
  • Key:XRXDAJYKGWNHTQ-UHFFFAOYSA-N ☒N
  (verify)

Quipazine, also known as 1-(2-quinolinyl)piperazine (2-QP), is a serotonergic drug of the arylpiperazine family and an analogue of 1-(2-pyridinyl)piperazine which is used in scientific research.[2][3][4][5][6] It was first described in the 1960s and was originally intended as an antidepressant but was never developed or marketed for medical use.[2][7][5] The effects of quipazine in humans include nausea, vomiting, gastrointestinal disturbances, diarrhea, and, at higher doses, psychedelic effects.[2][1][4] Quipazine may represent the prototype of a novel structural class of psychedelic drugs.[2][8][9]

Effects

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The effects and side effects of quipazine in humans have been described.[1][2] At a dose of 25 mg orally, they included nausea, flatulence, gastrointestinal discomfort, and diarrhea, with no LSD-like subjective effects.[1] Higher doses were not assessed due to serotonin 5-HT3 receptor-mediated side effects of nausea and gastrointestinal discomfort.[1][4] An anecdotal report in one or more subjects, in which the dose of quipazine was said to be 0.5 mg (sic), described quipazine as producing low-dose mescaline-like effects followed by onset of dysphoria and nausea.[1][2][10]

It was suggested by Jerrold C. Winter in 1994 that serotonin 5-HT3 receptor antagonists like ondansetron could allow for use of higher doses of quipazine and assessment of whether it produces clear psychedelic effects or not.[1] Alexander Shulgin subsequently reported in The Shulgin Index (2011), based on an anonymous report dated to 2007, that quipazine in combination with a serotonin 5-HT3 receptor antagonist, presumably ondansetron, produced a "full psychedelic response".[4][11][2][12]

Interactions

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See also: Psychedelic drug § Interactions, and Trip killer § Serotonergic psychedelic antidotes

Serotonin 5-HT3 receptor antagonists like ondansetron have been reported to block the nausea and vomiting induced by quipazine.[4][11][2][12] Serotonin 5-HT2A receptor antagonists like ketanserin have been reported to block the psychedelic-like effects of quipazine in animals.[2][4]

Pharmacology

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Pharmacodynamics

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Quipazine activities[13]
Target Affinity (Ki, nM)
5-HT1A 230–>10,000
5-HT1B 1,000
5-HT1D 1,000–3,720
5-HT1E ND
5-HT1F ND
5-HT2A 59–2,780 (Ki)
309 (EC50Tooltip half-maximal effective concentration)
62–71% (EmaxTooltip maximal efficacy)
5-HT2B 49–178 (Ki)
178 (EC50)
17% (Emax)
5-HT2C 54–1,344 (Ki)
339 (EC50)
57–69% (Emax)
5-HT3 1.23–4.0 (Ki)
1.0 (EC50)
ND (Emax)
5-HT4 >10,000 (guinea pig)
5-HT5A >10,000 (mouse)
5-HT6 3,600
5-HT7 3,033
α1 >10,000 (rat)
α2 5,000 (rat)
β1 5,600
β2 2,900 (rat)
D1 >10,000
D2 >10,000
D2-like 3,920 (rat)
mAChTooltip Muscarinic acetylcholine receptor >10,000 (rat)
TAAR1Tooltip Trace amine-associated receptor 1 >10,000 (human) (EC50)
SERTTooltip Serotonin transporter 30–143
NETTooltip Norepinephrine transporter ND
DATTooltip Dopamine transporter ND
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [14][15][13][16][17][18][19][20][21]

Quipazine is a serotonin 5-HT3 receptor agonist and to a lesser extent a serotonin 5-HT2A, 5-HT2B, 5-HT2C receptor agonist and serotonin reuptake inhibitor.[2][3][17][14][15] Activation of the serotonin 5-HT3 is implicated in inducing nausea and vomiting as well as anxiety, which has limited the potential clinical usefulness of quipazine.[2][3][4]

Quipazine produces a head-twitch response and other psychedelic-consistent effects in animal studies including in mice, rats, and monkeys.[2][4][22][23][24] These effects appear to be mediated by activation of the serotonin 5-HT2A receptor, as they are blocked by serotonin 5-HT2A receptor antagonists like ketanserin.[2][4][24] The head twitches induced by quipazine are potentiated by the monoamine oxidase inhibitor (MAOI) pargyline.[24][25] Based on this, it has been suggested that quipazine may act as a serotonin releasing agent and that it may induce the head twitch response by a dual action of serotonin 5-HT2A receptor agonism and induction of serotonin release.[24][25]

Besides the head-twitch response, quipazine fully substitutes for LSD and partially substitutes for mescaline in rodent drug discrimination tests.[1] In addition, quipazine substitutes for DOM in rodents and monkeys and this is blocked by serotonin 5-HT2A receptor antagonists like pizotyline and ketanserin.[2] When quipazine is used as the training drug, LSD, mescaline, and psilocybin all fully substitute for quipazine.[2] In monkeys, quipazine additionally produced LSD-like behavioral changes along with projectile vomiting.[1] In contrast to primates, rodents generally lack an emetic response, and hence the nausea and vomiting that quipazine can induce may not be a limiting factor in this order of animals.[2] Similarly to DOI, quipazine alters time perception in rodents.[26]

Quipazine can produce tachycardia, including positive chronotropic and positive inotropic effects, through activation of the serotonin 5-HT3 receptor.[3]

Although quipazine does not generalize to dextroamphetamine in drug discrimination tests of dextroamphetamine-trained rodents, dextroamphetamine and cathinone have been found to partially generalize to quipazine in assays of quipazine-trained rodents.[27][28] In relation to this, it has been suggested that quipazine might possess some dopaminergic activity, as the discriminative stimulus properties of amphetamine appear to be mediated by dopamine signaling.[27][28] Relatedly, quipazine has been said to act as a dopamine receptor agonist in addition to serotonin receptor agonist.[24] Conversely however, the generalization may be due to serotonergic activities of amphetamine and cathinone.[29] Fenfluramine has been found to fully generalize to quipazine, but levofenfluramine, in contrast to quipazine, did not generalize to dextroamphetamine.[27][23]

Quipazine is said to differ in its pharmacology and effects from other serotonergic arylpiperazines like TFMPP and mCPP.[2][4] Relatedly, unlike quipazine, neither TFMPP nor mCPP substitute for DOM in drug discrimination tests.[2][4] In addition, DOM and TFMPP mutually antagonize each others' stimulus effects.[2] In contrast to quipazine, TFMPP and mCPP show prominent bias or preference for the serotonin 5-HT2C receptor over the serotonin 5-HT2A receptor.[4]

Quipazine is a very weak agonist of the human trace amine-associated receptor 1 (TAAR1).[21]

Chemistry

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Quipazine is a substituted piperazine and quinoline.[5] It is structurally related to 6-nitroquipazine, isoquipazine, 1-(2-naphthyl)piperazine (2-NP), and 1-(1-naphthyl)piperazine (1-NP).[5][4]

Novel analogues of quipazine with retained serotonin 5-HT2A receptor agonism and reduced undesirable off-target activity such as serotonin 5-HT3 receptor agonism and associated adverse effects have been developed and characterized.[8][9]

Synthesis

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Quipazine synthesis.[30]

Quipazine is synthesized by reacting 2-chloroquinoline with piperazine.[30]

History

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Quipazine was first described in the scientific literature by 1966.[5][31] It was described as an antidepressant-like agent by 1971.[7] The psychedelic-like effects of quipazine in animals were first described by 1977.[25]

See also

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References

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  1. ^ a b c d e f g h i Winter JC (1994). "The stimulus effects of serotonergic hallucinogens in animals" (PDF). NIDA Res Monogr. 146: 157–182. PMID 8742798.
  2. ^ a b c d e f g h i j k l m n o p q r s Glennon RA, Dukat M (2 May 2023). "Quipazine: Classical hallucinogen? Novel psychedelic?". Australian Journal of Chemistry. 76 (5): 288–298. doi:10.1071/CH22256. ISSN 0004-9425.
  3. ^ a b c d Cappelli A, Butini S, Brizzi A, Gemma S, Valenti S, Giuliani G, et al. (2010). "The interactions of the 5-HT3 receptor with quipazine-like arylpiperazine ligands: the journey track at the end of the first decade of the third millennium". Curr Top Med Chem. 10 (5): 504–526. doi:10.2174/156802610791111560. PMID 20166948.
  4. ^ a b c d e f g h i j k l m de la Fuente Revenga M, Shah UH, Nassehi N, Jaster AM, Hemanth P, Sierra S, et al. (March 2021). "Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice". ACS Chem Neurosci. 12 (5): 831–844. doi:10.1021/acschemneuro.0c00291. PMC 7933111. PMID 33400504.
  5. ^ a b c d e Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 987. ISBN 978-1-4757-2085-3. Retrieved 10 December 2024.
  6. ^ Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 244. ISBN 978-94-011-4439-1. Retrieved 10 December 2024.
  7. ^ a b Rodríguez R, Pardo EG (1971). "Quipazine, a new type of antidepressant agent". Psychopharmacologia. 21 (1): 89–100. doi:10.1007/BF00404000. PMID 5567294.
  8. ^ a b Psychedelic Alpha (20 March 2024). "Notes from the International Society for Research on Psychedelics' 2024 Conference in New Orleans (Guest Contribution)". Psychedelic Alpha. Retrieved 10 May 2025. Dr. Jason Younkin, a postdoctoral researcher at Virginia Commonwealth University and adjunct professor at Virginia State University, gave a talk and displayed interesting findings with quipazine analogs during the poster session. Quipazine is a unique psychedelic as its chemical structure includes a piperazine group. While it produces psychedelic effects, it is not used as frequently as other serotonergic psychedelics due to its effects on the gastrointestinal tract via 5-HT3 receptor activation. The goal of this study was to find analogs of quipazine that do not produce these negative side effects or the hallucination-like effects of all classical psychedelics using a battery of molecular and pharmacological techniques. [Photograph]
  9. ^ a b Jason Younkin (16 February 2024). Pharmacological characterization of quipazine analogs as a new structural class of psychedelic 5-HT2A receptor agonists. International Society for Research on Psychedelics.
  10. ^ Winter JC (February 1979). "Quipazine-induced stimulus control in the rat". Psychopharmacology (Berl). 60 (3): 265–269. doi:10.1007/BF00426666. PMID 108704. As yet, no report of the effects of quipazine in human subjects has been published. The implications of the present findings and those of White et al. (1977) for the clinical pharmacology of quipazine are obvious. One would expect the drug to produce at least a portion of the mescaline-LSD syndrome. In a preliminary clinical investigation (H. Daumier, personal communication) normal human subjects reported 'low dose mescaline-like' effects at a dose of 0.5 mg. The study of higher doses was precluded by the onset of dysphoric effects including nausea.
  11. ^ a b Halberstadt AL, Geyer MA (2016). "Effect of Hallucinogens on Unconditioned Behavior". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 159–199. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. PMC 5787039. PMID 28224459.
  12. ^ a b Shulgin A, Manning T, Daley P (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. p. 34. ISBN 978-0-9630096-3-0. Retrieved 2 November 2024. Quipazine [...] (11) This experimental antidepressant is an agonist to several 5-HT2 and 5-HT3 receptors. If taken with a 5-HT3 antagonist, quipazine (blocking nausea/vomiting) it produces a full psychedelic response (Anon., 2007).
  13. ^ a b Butler JJ, Ricci D, Aman C, Beyeler A, De Deurwaerdère P (November 2024). "Classical psychedelics' action on brain monoaminergic systems". Int J Biochem Cell Biol. 176: 106669. doi:10.1016/j.biocel.2024.106669. PMID 39332625.
  14. ^ a b "PDSP Database". UNC (in Zulu). Retrieved 4 December 2024.
  15. ^ a b Liu T. "BindingDB BDBM50014407 2-(piperazin-1-yl)quinoline::2-Piperazin-1-yl-quinoline::2-Piperazin-1-yl-quinoline (Quipazine)::2-Piperazin-1-yl-quinoline(Quipazine)::CHEMBL18772::QUIPAZINE". BindingDB. Retrieved 4 December 2024.
  16. ^ Nelson DL (December 1991). "Structure-activity relationships at 5-HT1A receptors: binding profiles and intrinsic activity". Pharmacol Biochem Behav. 40 (4): 1041–1051. doi:10.1016/0091-3057(91)90124-k. PMID 1816558.
  17. ^ a b Egan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, et al. (February 2000). "Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors". Synapse. 35 (2): 144–150. doi:10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K. PMID 10611640.
  18. ^ Cappelli A, Giuliani G, Gallelli A, Valenti S, Anzini M, Mennuni L, et al. (May 2005). "Structure-affinity relationship studies on arylpiperazine derivatives related to quipazine as serotonin transporter ligands. Molecular basis of the selectivity SERT/5HT3 receptor". Bioorg Med Chem. 13 (10): 3455–3460. doi:10.1016/j.bmc.2005.03.008. PMID 15848758.
  19. ^ Jarończyk M, Wołosewicz K, Gabrielsen M, Nowak G, Kufareva I, Mazurek AP, et al. (March 2012). "Synthesis, in vitro binding studies and docking of long-chain arylpiperazine nitroquipazine analogues, as potential serotonin transporter inhibitors". Eur J Med Chem. 49: 200–210. doi:10.1016/j.ejmech.2012.01.012. PMC 3365592. PMID 22309909.
  20. ^ Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, et al. (September 1999). "Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells". Br J Pharmacol. 128 (1): 13–20. doi:10.1038/sj.bjp.0702751. PMC 1571597. PMID 10498829.
  21. ^ a b Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D (January 2024). "Molecular basis of human trace amine-associated receptor 1 activation". Nat Commun. 15 (1): 108. Bibcode:2024NatCo..15..108Z. doi:10.1038/s41467-023-44601-4. PMC 10762035. PMID 38168118.
  22. ^ Glennon RA (1996). "Classical Hallucinogens". Pharmacological Aspects of Drug Dependence. Handbook of Experimental Pharmacology. Vol. 118. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 343–371. doi:10.1007/978-3-642-60963-3_10. ISBN 978-3-642-64631-7.
  23. ^ a b Glennon RA (1988). "Site-Selective Serotonin Agonists as Discriminative Stimuli". Transduction Mechanisms of Drug Stimuli. Psychopharmacology Series. Vol. 4. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 15–31. doi:10.1007/978-3-642-73223-2_2. ISBN 978-3-642-73225-6. PMID 3293039.
  24. ^ a b c d e Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, et al. (January 2004). "Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives". Neurotoxicology. 25 (1–2): 223–232. Bibcode:2004NeuTx..25..223N. doi:10.1016/S0161-813X(03)00101-3. PMID 14697897.
  25. ^ a b c Malick JB, Doren E, Barnett A (March 1977). "Quipazine-induced head-twitch in mice". Pharmacol Biochem Behav. 6 (3): 325–329. doi:10.1016/0091-3057(77)90032-6. PMID 140381.
  26. ^ Akhmirov R, Mitiureva D, Zaichenko M, Smirnov K, Sysoeva O (December 2024). "The Role of the Serotonergic System in Time Perception: A Systematic Review". Int J Mol Sci. 25 (24): 13305. doi:10.3390/ijms252413305. PMC 11679555. PMID 39769070.
  27. ^ a b c Young R, Glennon RA (1986). "Discriminative stimulus properties of amphetamine and structurally related phenalkylamines". Med Res Rev. 6 (1): 99–130. doi:10.1002/med.2610060105. PMID 3512936.
  28. ^ a b Glennon RA, Rosecrans JA (1981). "Speculations on the mechanism of action of hallucinogenic indolealkylamines". Neurosci Biobehav Rev. 5 (2): 197–207. doi:10.1016/0149-7634(81)90002-6. PMID 7022271.
  29. ^ Goudie AJ (September 1985). "Comparative effects of cathinone and amphetamine on fixed-interval operant responding: a rate-dependency analysis". Pharmacol Biochem Behav. 23 (3): 355–365. doi:10.1016/0091-3057(85)90006-1. PMID 4048231.
  30. ^ a b DE 2006638, Rodriguez R, issued 1970  Chem. Abstr., 73: 98987g (1970).
  31. ^ Salas M, Cervantes M, Guzman-Flores C (1966). "Mechanism of action of quipazine maleate on the central nervous system". Bol Inst Estud Med Biol Univ Nac Auton Mex. 24 (1): 191–205. PMID 5299393.
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