Pip-Tryptamine

Pharmaceutical compound From Wikipedia, the free encyclopedia

pip-Tryptamine (pip-T), also known as N,N-pentamethylenetryptamine, N,N-piperidyltryptamine, or 3-(2-piperidinoethyl)indole, is a serotonin receptor modulator and possible serotonergic psychedelic of the tryptamine family.^[1]^[2]^[3]^[4]^[5]^[6] It is the derivative of tryptamine in which the amine has been cyclized into a piperidine ring.^[1]^[2]^[3]

Other names3-(2-Piperidinoethyl)indole; N-Piperidyltryptamine; N,N-Piperidyltryptamine; Piperidinyltryptamine; Piperidinotryptamine; PIT; N,N-Pentamethylenetryptamine

Drug classSerotonin receptor modulator

ATC code

None

CAS Number

26628-87-5

Quick facts Clinical data, Other names ...

pip-Tryptamine
Clinical data


Other names	3-(2-Piperidinoethyl)indole; N-Piperidyltryptamine; N,N-Piperidyltryptamine; Piperidinyltryptamine; Piperidinotryptamine; PIT; N,N-Pentamethylenetryptamine
Drug class	Serotonin receptor modulator
ATC code	None
Identifiers
IUPAC name 3-(2-piperidin-1-ylethyl)-1H-indole
CAS Number	26628-87-5
PubChem CID	33560
ChemSpider	30961
ChEMBL	ChEMBL2138465
CompTox Dashboard (EPA)	DTXSID70181173
Chemical and physical data
Formula	C₁₅H₂₀N₂
Molar mass	228.339 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C1CCN(CC1)CCC2=CNC3=CC=CC=C32
InChI InChI=1S/C15H20N2/c1-4-9-17(10-5-1)11-8-13-12-16-15-7-3-2-6-14(13)15/h2-3,6-7,12,16H,1,4-5,8-11H2 Key:PJVCNRSWJSLGCV-UHFFFAOYSA-N

Use and effects

pip-T was only briefly mentioned by Alexander Shulgin in his book TiHKAL (Tryptamines I Have Known and Loved).^[2] Its properties and effects were not described.^[2]

Interactions

Pharmacology

Pharmacodynamics

The affinities (IC₅₀Tooltip half-maximal inhibitory concentration) of pip-tryptamine for serotonin receptors were 600 nM for the serotonin 5-HT_1A receptor, 760 nM for the serotonin 5-HT_2A receptor, and 1,250 nM for the serotonin 5-HT_2B receptor, whereas other serotonin receptors were not reported.^[1]^[3] The affinity of pip-T for the serotonin 5-HT_2A receptor was about 10-fold lower than that of dimethyltryptamine (DMT) and was about 7-fold lower than that of pyr-tryptamine (pyr-T; N,N-pyrrolidinyltryptamine).^[3]

The drug produces hypolocomotion in rodents.^[4] In addition, it induces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.^[4] This was blocked by the serotonin 5-HT_2A receptor antagonist ketanserin.^[4] Hence, the drug may have hallucinogenic effects in humans.^[4] Conversely, pip-T did not produce conditioned place preference (CPP) and was not self-administered, suggesting that it lacks reinforcing properties and misuse potential, similarly to most other tryptamines.^[4]

Chemistry

Synthesis

The chemical synthesis of pip-T has been described.^[2]

Analogues

Analogues of pip-T include 5-MeO-pip-T, 10,11-secoergoline (α,N-Pip-T), pyr-T, MPMI, SN-22, RU-24,969, and EMD-386088, among others.

mor-Tryptamine

mor-Tryptamine, or mor-T, also known as 3-(2-morpholinoethyl)indole, is the analogue of pip-T with the piperidine ring replaced with a morpholine ring.^[2] It was briefly described by Alexander Shulgin in his book TiHKAL (Tryptamines I Have Known and Loved), including its chemical synthesis.^[2] The drug was tested by intramuscular injection of 30 mg as the fumarate salt, but produced no effects whatsoever.^[2] The 5-methoxy derivative of mor-T, 5-MeO-mor-T, is also known, but is not known to have been tested.^[2]

History

Pip-T was first described in the scientific literature by 1959^[5] and was more thoroughly characterized in 1990^[1]^[3] and 2020.^[4]

References

[1]
Nichols DE (2018). "Chemistry and Structure–Activity Relationships of Psychedelics". Behavioral Neurobiology of Psychedelic Drugs. Curr Top Behav Neurosci. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524. A systematic study of the effect of N-alkylation on tryptamine receptor affinities was reported by McKenna et al. (1990). N-alkylated tryptamines were examined with no ring substituents, a 5-methoxy, or 4-hydroxy group. Highest affinities (4–30 nM) for displacement of [125I]DOI from rat cortical homogenate were observed with N,N-dimethyl, N,N-diethyl, N-methyl-N-isopropyl, and N,N-diisopropyl substituents. An affinity of 39 nM was reported for 4-OH-N,N-di(sec-butyl) tryptamine, but the affinity of 4-OH-N,N-diisobutyltryptamine was only 260 nM. Tethering the dialkyl groups into a heterocyclic ring gave mixed results; N-pyrrolidyl had an affinity similar to N,N-dimethyltryptamine (110 vs. 75 nM, respectively), but the affinity for the N-piperidyl was much lower, at 760 nM. {{cite book}}: |journal= ignored (help)
[2]
Alexander T. Shulgin; Ann Shulgin (1991). "#52. PYR-T TRYPTAMINE, N,N-TETRAMETHYLENE; INDOLE, 3-[2-(1-PYRROLIDYL)ETHYL]; PYRROLIDINE, 1-[2-(3-INDOLYL)ETHYL]; N,N-TETRAMETHYLENETRYPTAMINE; 1-[2-(1H-INDOL-3-YL)ETHYL]PYRROLIDINE; 1-[2-(1-PYRROLIDYL)ETHYL]INDOLE; "PYRROLIDYLTRYPTAMINE"". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. pp. 577–578. ISBN 978-0-9630096-0-9. OCLC 25627628. EXTENSIONS AND COMMENTARY: First of all, the name pyr-T, which is an abbreviation for "pyrrolidinyltryptamine," is out-and-out wrong. There is just one single nitrogen at the end of the tryptamine chain and it cannot be claimed by both halves of the name. It is intrinsic to the name pyrrolidine as well as to the name tryptamine. This is why the name is in quotation marks. This drug has occasionally been called PT in the popular literature, but choosing to spell it out as pyr-T allows a parallel code to be used with the piperidine and morpholine analogues. These two analogues are both described in the literature. The piperidine material (pip-T) is made via the glyoxylamide (mp 182-183 °C) which is reduced with LAH to the target amine (mp 149-150 °C, HC1 salt 220-221 °C). The morpholine analogue (mor-T) also came to be via the glyoxylamide (mp 187-188 °C) and the reduction to the amine which can be an oil, but which has been reported to have a mp 145- 147 °C. The only trials I know of with either of these is with mor-T which, as the fumarate salt, had no effects at all upon the i.m. injection of a 30 milligram bolus. Actually, this neat trilogy of heterocyclics, the pyrrolidine ring, the piperidine ring, and the morpholine ring, have been the chemist's favorite for many years. Leaf through the "Known Tryptamines" appendix, and see how often you see stretched between the nitrogen substituents the phrases: [...]
[3]
McKenna DJ, Repke DB, Lo L, Peroutka SJ (March 1990). "Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes". Neuropharmacology. 29 (3): 193–198. doi:10.1016/0028-3908(90)90001-8. PMID 2139186.
[4]
Abiero A, Ryu IS, Botanas CJ, Custodio RJ, Sayson LV, Kim M, Lee HJ, Kim HJ, Seo JW, Cho MC, Lee KW, Yoo SY, Jang CG, Lee YS, Cheong JH (January 2020). "Four Novel Synthetic Tryptamine Analogs Induce Head-Twitch Responses and Increase 5-HTR2a in the Prefrontal Cortex in Mice". Biomol Ther (Seoul). 28 (1): 83–91. doi:10.4062/biomolther.2019.049. PMC 6939696. PMID 31230432.
[5]
Barlow RB, Khan I (March 1959). "Actions of some analogues of tryptamine on the isolated rat uterus and on the isolated rat fundus strip preparations". Br J Pharmacol Chemother. 14 (1): 99–107. doi:10.1111/j.1476-5381.1959.tb00934.x. PMC 1481812. PMID 13651585.
[6]
Cami-Kobeci G, Slatford PA, Whittlesey MK, Williams JM (February 2005). "N-Alkylation of phenethylamine and tryptamine". Bioorg Med Chem Lett. 15 (3): 535–537. doi:10.1016/j.bmcl.2004.11.050. PMID 15664808. We were pleased to find that reaction of tryptamine (12) with the appropriate diol (16, 23 and 24) resulted in good conversion to the corresponding pyrrolidine 25, and piperidine 26, and in reasonable isolated yield into azepane 27 (Scheme 6).