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LA-Pip

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LA-Pip
Clinical data
Other namesLSD-Pip; N-Piperidinyllysergamide; N-Piperidine lysergamide; LA-Pip; LSDPip; LAPip; 6-Methyl-8β-(piperidin-1-ylcarbonyl)-9,10-didehydroergoline
Drug classSerotonin receptor modulator
Identifiers
  • [(6aR,9R)-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinolin-9-yl]-piperidin-1-ylmethanone
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H25N3O
Molar mass335.451 g·mol−1
3D model (JSmol)
  • CN1C[C@@H](C=C2[C@H]1Cc3c[nH]c4c3c2ccc4)C(=O)N5CCCCC5
  • InChI=1S/C21H25N3O/c1-23-13-15(21(25)24-8-3-2-4-9-24)10-17-16-6-5-7-18-20(16)14(12-22-18)11-19(17)23/h5-7,10,12,15,19,22H,2-4,8-9,11,13H2,1H3/t15-,19-/m1/s1
  • Key:URDULHYODQAQTM-DNVCBOLYSA-N
  (verify)

Lysergic acid piperidide (LA-Pip or LSD-Pip), also known as N-piperidinyllysergamide, is a serotonin receptor modulator of the lysergamide family related to lysergic acid diethylamide (LSD).[1][2][3] It is the analogue of LSD in which the N,N-diethyl substitution has been replaced with an N-piperidide ring.[2][3][4]

The drug has fairly similar affinity and efficacy as a serotonin 5-HT2A receptor agonist compared to LSD, though is variably less potent in terms of EC50Tooltip half-maximal effective concentration depending on the assay.[2][1][3][4] It also has high affinity for the serotonin 5-HT1A and 5-HT2C receptors.[1][3][4] LA-Pip has about 8.5% of the antiserotonergic activity of LSD (relative to 2.0% for LSM-775 and 4.7% for LPD-824) in the isolated rat uterus in vitro.[5][6][7]

LA-Pip has been said to be non-hallucinogenic or much less psychedelic than LSD in humans.[1][8][9] However, this does not appear to have actually been stated anywhere in the originally cited source.[6] Other sources imply that LA-Pip has not been assessed in humans.[5] Correspondingly, the dose range and potency of LA-Pip as a psychedelic relative to LSD have not been reported.[5][7]

LA-Pip was first described in the scientific literature by Albert Hofmann and colleagues by 1955.[10][6][11][12] There were additional publications on the compound in the later 1950s.[13][14][15] It has not been encountered as a designer drug as of 2020.[13]

See also

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References

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  1. ^ a b c d Parrish JC (30 October 2007). "Toward a molecular understanding of hallucinogen action". Purdue e-Pubs. From the results of the experiments outlined under specific aim 1, we may be led to conclude that relative 5-HT2A receptor-dependent IP accumulation is a good predictor of the hallucinogenic potency of 5-HT 2A receptor agonists. If one looks beyond the phenethylamines, however, to the tryptamines and ergolines, the present data refute this conjecture. For example, upon analyzing a series of ergoline compounds (Appendix) we find that LSD, one of the most potent hallucinogens, is a poor stimulator of IP accumulation. In fact, the piperidide derivative of lysergic acid (LA-Pip), which lacks significant hallucinogenic potency (Cerletti and Doepfner 1958), was found to be a better agonist for IP accumulation relative to LSD (Appendix). If IP accumulation was correlated to hallucinogenesis, one would predict that LA-Pip would be an even more potent hallucinogen than LSD. [...] A series of LSD derivatives was characterized for competition binding and IP accumulation relative to LSD (Fig. A.1). The LA-Pip derivative was approximately a third as potent as LSD but had roughly twice the intrinsic activity of LSD for IP accumulation. Although the LA-Pip derivative has roughly twice the affinity relative to LSD for the human 5-HT 1A receptor, its 5-HT 2A and 5-HT 2C receptor affinities are comparable Curiously this compound is inactive in man (Cerletti and Doepfner 1958). [...] Figure A.1 The series of amide substituted LSD derivatives used in this study. [...] Table A.1 Results of competition binding experiments and IP accumulation assays for the series of ergolines illustrated in Figure A.1. [...]
  2. ^ a b c Braden MR (2007). Towards a biophysical understanding of hallucinogen action (Ph.D. thesis). Purdue University. ProQuest 304838368. Table 4.7 Effect of the N6.55(343)A mutation on binding to the h5-HT2A receptor. [...] Table 4.8 Effect of the N6.55(343)A mutation on h5-HT2A receptor-mediated PI hydrolysis.
  3. ^ a b c d Nichols DE (2018). Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524. Table 1 5-HT2A 5-HT2C, and 5-HT1A receptor affinity and functional effects for selected lysergamides [...] R'/R: Piperidide [...]
  4. ^ a b c Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi:10.1002/wmts.42. ISSN 2190-460X. TABLE 1 5-HT2A Receptor Affinity and Functional Effects of Selected Lysergamides1 [...] Compound Number: 25. Amide R,R Groups: –(CH2)5–. 5-HT2A2: 12.2 ± 0.2. 5-HT2C3: 6.1 ± 0.5. 5-HT1A4: 0.66 ± 0.08. IP3 (EC50): 140 ± 26 (33.7 ± 5.1%). [...] 1 Data from Parrish.42. [...] 42. Parrish JC. Toward a molecular understanding of hallucinogen action. 2006. Purdue University.
  5. ^ a b c Oberlender RA (May 1989). "Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens". Purdue e-Pubs. Purdue University. Table 2. Relative potency values for lysergic acid amides. [...] Cyclic Amides: [...] R2/R3: -CH2CH2CH2CH2CH2CH2- (Piperidide). Potency relative to LSDa: From studies employing: Humanb: ?. In Vitroc: 8.5[%]. [...] aRelative potency for both assays are expressed in terms of percent of LSD's potency. A value of 50 indicates one half as potent as LSD. bHuman potency values compiled by Shulgin (1981; 1982). References for the individual studies can be found in these reports. c In vitro values represent serotonin antagonist potency as evaluated by Cerletti and Doepfner (1958) in the isolated rat uterus. [...] Two cyclized amides have been evaluated in humans. The pyrrolidide represents an LSD derivative in which an additional carbon-carbon bond connects the β-carbons of the two ethyl groups. The morpholide can be viewed as a derivative in which these same carbons are bridged by an oxygen. Both of these compounds were about one third as potent as LSD.
  6. ^ a b c Cerletti A, Doepfner W (January 1958). "Comparative Study on the Serotonin Antagonism of Amide Derivatives of Lysergic Acid and of Ergot Alkaloids". The Journal of Pharmacology and Experimental Therapeutics. 122 (1): 124–136. doi:10.1016/S0022-3565(25)11933-2. PMID 13502837. Archived from the original on 25 March 2025. 4. Cyclic amide derivatives of lysergic acid. The four compounds listed in section C of table 1 can be considered as having the two aminoethyl groups closed to form a five- or six-membered ring. Although some of the pharmacologic effects of LSD are enhanced by this ring formation (for example, the depressor effect of the pyrrolidide and pyrrolinide is stronger than with LSD (Cerletti, 1955), the antiserotonin activity is reduced ten to fifty times as compared with LSD. [...] TABLE 1 Antiserotonin potency of 16 amide-derivatives of d-lysergic acid [...] C. Cyclic amide, derivatives: R = [...] Name: d-lysergic acid piperidid. Relative activity ± s.e.* (LSD = 100) %: 8.5 ± 1.6.
  7. ^ a b Gupta SP, Singh P, Bindal MC (1 December 1983). "QSAR studies on hallucinogens". Chemical Reviews. 83 (6): 633–649. doi:10.1021/cr00058a003. ISSN 0009-2665. TABLE XII. Antiserotonin and Hallucinogenic Activities and Hückel's Total MO Energy of LSD and its Analogues [...] Data collected by Kumbar and Siva Sankar,91,92 from ref 70a, 87, 88, and 90; all activities are relative to that of LSD taken as 100.
  8. ^ Nichols DE (2001). "LSD and Its Lysergamide Cousins" (PDF). The Heffter Review of Psychedelic Research. 2. Heffter Research Institute: 80–87. ISSN 1534-9640. The two ethyl groups were incorporated into ring structures such as the pyrrolidide, piperidide, and morpholide, shown above, but these also had reduced anti-serotonin and psychedelic effects (Cerletti and Doepfner 1958). Although the morpholide had less than one-tenth of the potency of LSD in blocking the action of serotonin, it did however have nearly 75% of the potency of LSD as a psychedelic (Gogerty and Dille 1957).
  9. ^ Valter K, Arrizabalaga P (16 October 1998). Designer Drugs Directory. Elsevier. p. 79. ISBN 978-0-08-053032-1. Retrieved 5 June 2025. Most of the other LSD analogues (e.g. piperidide, pyrrolidide) show very low or negligible LSD-like activity in humans [6]. Only two LSD analogues have recently been reported to be more potent psychotomimetics than LSD itself However, there is no evidence of their eventual abuse or clandestine manufacture.
  10. ^ Stoll A, Hofmann A (1955). "Amide der stereoisomeren Lysergsäuren und Dihydro-lysergsäuren. 38. Mitteilung über Mutterkornalkaloide" [Amides of stereoisomeric lysergic and dihydrolysergic acids. 38. Ergot alkaloids]. Helvetica Chimica Acta. 38 (2): 421–433. doi:10.1002/hlca.19550380207. ISSN 0018-019X. Retrieved 5 June 2025.
  11. ^ Hofmann A (1958). "The LSD-Psychosis: III. Lysergic Acid Diethylamide and Related Compounds. Relationship Between Spatial Arrangement and Mental Effects". In Rinkel M (ed.). Chemical Concepts of Psychosis: Proceedings of the Symposium on Chemical Concepts of Psychosis held at the Second International Congress of Psychiatry in Zurich, Switzerland, September 1 to 7, 1957. New York: McDowell, Obolensky. pp. 85–90. doi:10.1037/11190-006. Archived from the original on 4 June 2025. TABLE I Variations in the acid amide group of the LSD molecule. Amides of d-lysergic acid (C15H15N2.COR) prepared for pharmacological investigation. [...] R: [...] d-lysergic acid piperidine. [...]
  12. ^ Hofmann A (June 1959). "Psychotomimetic drugs; chemical and pharmacological aspects" (PDF). Acta Physiologica et Pharmacologica Neerlandica. 8: 240–258. PMID 13852489.
  13. ^ a b Brandt SD, Kavanagh PV, Westphal F, Stratford A, Elliott SP, Dowling G, et al. (October 2020). "Analytical profile of N-ethyl-N-cyclopropyl lysergamide (ECPLA), an isomer of lysergic acid 2,4-dimethylazetidide (LSZ)". Drug Testing and Analysis. 12 (10): 1514–1521. doi:10.1002/dta.2911. PMC 9191644. PMID 32803833. The isomeric relationship between (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ), and ECPLA (Figure 1) prompted the investigation of analytical features that can be used to differentiate between these two lysergamides. At the same time, it is worth noting that in addition to ECPLA and LSZ, several other isomeric lysergamides have been described in the scientific literature (although information about their availability or use as recreational drugs is not available). Three examples reflecting the C21H25N3O formula (MW 335.45 g/mol) include lysergic acid piperidide (LA-Pip), 1-methyl-N-pyrrolidyllysergamide (MPD-75), and lysergic acid cyclopentylamide (Cepentyl), respectively. Although some chemical and pharmacological descriptions of these three compounds are available (Table S1, Supporting Information), it is unclear whether they are likely to be the focus of future research and/or whether they will appear as new recreational drugs. [...] Table S1. Three examples also reflecting the C21H25N3O formula (Mw 335.45 g/mol) [...] Compound: LSD-Pip; LA-Pip; Lysergic acid piperidide; N-Piperidinyllysergamide. Chemistry: 1-5. Pharmacology: 6-10.
  14. ^ GB 785173, Smith G, "Amide-like derivatives of lysergic and isolysergic acids", published 1957-10-02, assigned to Burroughs Wellcome and Co 
  15. ^ US 2997470, Pioch RP, "Lysergic acid amides", issued 1961-08-22, assigned to Eli Lilly and Company 
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