Quipazine

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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.[1][2][3][4][5] It was first described in the 1960s and was originally intended as an antidepressant but was never developed or marketed for medical use.[1][6][4] The effects of quipazine in humans include nausea, vomiting, gastrointestinal disturbances, diarrhea, and, at higher doses, psychedelic effects.[1][7][3] Quipazine may represent the prototype of a novel structural class of psychedelic drugs.[1][8][9]

Effects

The effects and side effects of quipazine in humans have been described.[7][1] At a dose of 25Script error: No such module "String".mg orally, they included nausea, flatulence, gastrointestinal discomfort, and diarrhea, with no LSD-like subjective effects.[7] Higher doses were not assessed due to serotonin 5-HT3 receptor-mediated side effects of nausea and gastrointestinal discomfort.[7][3] An anecdotal report in one or more subjects, in which the dose of quipazine was said to be 0.5Script error: No such module "String".mg (sic), described quipazine as producing low-dose mescaline-like effects followed by onset of dysphoria and nausea.[7][1][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.[7] 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".[3][11][1][12]

Interactions

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Serotonin 5-HT3 receptor antagonists like ondansetron have been reported to block the nausea and vomiting induced by quipazine.[3][11][1][12] Serotonin 5-HT2A receptor antagonists like ketanserin have been reported to block the psychedelic-like effects of quipazine in animals.[1][3]

Pharmacology

Pharmacodynamics

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, and 5-HT2C receptor agonist as well as serotonin reuptake inhibitor.[1][2][17][14][15] It also shows affinity for serotonin 5-HT1 receptors, including the serotonin 5-HT1B receptor and to a lesser extent the serotonin 5-HT1A receptor.[22] 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.[1][2][3]

Quipazine produces a head-twitch response and other psychedelic-consistent effects in animal studies including in mice, rats, and monkeys.[1][3][23][24][25] 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.[1][3][25] The head twitches induced by quipazine are potentiated by the monoamine oxidase inhibitor (MAOI) pargyline.[25][26] 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.[25][26]

Besides the head-twitch response, quipazine fully substitutes for LSD and partially substitutes for mescaline in rodent drug discrimination tests.[7] In addition, quipazine substitutes for DOM in rodents and monkeys and this is blocked by serotonin 5-HT2A receptor antagonists like pizotyline and ketanserin.[1] When quipazine is used as the training drug, LSD, mescaline, and psilocybin all fully substitute for quipazine.[1] In monkeys, quipazine additionally produced LSD-like behavioral changes along with projectile vomiting.[7] 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.[1] Similarly to DOI, quipazine alters time perception in rodents.[27]

Quipazine can produce tachycardia, including positive chronotropic and positive inotropic effects, through activation of the serotonin 5-HT3 receptor.[2]

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.[28][29] 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.[28][29] Relatedly, quipazine has been said to act as a dopamine receptor agonist in addition to serotonin receptor agonist.[25] Conversely however, the generalization may be due to serotonergic activities of amphetamine and cathinone.[30] Fenfluramine has been found to fully generalize to quipazine, but levofenfluramine, in contrast to quipazine, did not generalize to dextroamphetamine.[28][24]

Quipazine is said to differ in its pharmacology and effects from other serotonergic arylpiperazines like TFMPP and mCPP.[1][3] Relatedly, unlike quipazine, neither TFMPP nor mCPP substitute for DOM in drug discrimination tests.[1][3] In addition, DOM and TFMPP mutually antagonize each others' stimulus effects.[1] In contrast to quipazine, TFMPP and mCPP show prominent bias or preference for the serotonin 5-HT2C receptor over the serotonin 5-HT2A receptor.[3]

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

Chemistry

Quipazine is a substituted piperazine and quinoline.[4] It is structurally related to 6-nitroquipazine, isoquipazine, 1-(2-naphthyl)piperazine (2-NP), and 1-(1-naphthyl)piperazine (1-NP).[4][3]

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

File:Quipazine synthesis.svg
Quipazine synthesis.[31]

Quipazine is synthesized by reacting 2-chloroquinoline with piperazine.[31]

History

Quipazine was first described in the scientific literature by 1966.[4][32] It was described as an antidepressant-like agent by 1971.[6] The psychedelic-like effects of quipazine in animals were first described by 1977.[26]

See also

References

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  4. ↑ a b c d e Script error: No such module "citation/CS1".
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  6. ↑ a b Script error: No such module "Citation/CS1".
  7. ↑ a b c d e f g h Script error: No such module "Citation/CS1".
  8. ↑ a b Script error: No such module "citation/CS1".
  9. ↑ a b Script error: No such module "citation/CS1".
  10. ↑ Script error: No such module "Citation/CS1".
  11. ↑ a b Script error: No such module "citation/CS1".
  12. ↑ a b Script error: No such module "citation/CS1".
  13. ↑ a b Script error: No such module "Citation/CS1".
  14. ↑ a b Script error: No such module "citation/CS1".
  15. ↑ a b Script error: No such module "citation/CS1".
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  17. ↑ a b Script error: No such module "Citation/CS1".
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  20. ↑ Script error: No such module "Citation/CS1".
  21. ↑ a b Script error: No such module "Citation/CS1".
  22. ↑ Script error: No such module "Citation/CS1".
  23. ↑ Script error: No such module "citation/CS1".
  24. ↑ a b Script error: No such module "citation/CS1".
  25. ↑ a b c d e Script error: No such module "Citation/CS1".
  26. ↑ a b c Script error: No such module "Citation/CS1".
  27. ↑ Script error: No such module "Citation/CS1".
  28. ↑ a b c Script error: No such module "Citation/CS1".
  29. ↑ a b Script error: No such module "Citation/CS1".
  30. ↑ Script error: No such module "Citation/CS1".
  31. ↑ a b <templatestyles src="Citation/styles.css"/>Template:Citation/make link, Rodriguez R, issued Script error: No such module "auto date formatter". Script error: No such module "Check for unknown parameters". Chem. Abstr., 73: 98987g (1970).
  32. ↑ Script error: No such module "Citation/CS1".

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External links


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