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Comparative Study
. 2019 Mar;33(3):406-414.
doi: 10.1177/0269881119826610. Epub 2019 Feb 21.

Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice

Adam L Halberstadt  1   2 , Muhammad Chatha  1 , Stephen J Chapman  3 , Simon D Brandt  4
Affiliations
Comparative Study

Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice

Adam L Halberstadt et al. J Psychopharmacol. 2019 Mar.

Abstract

Background: In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. While a large amount of experimental work has been conducted to characterize the behavioral response to hallucinogens in rodents, there has been little systematic investigation of mescaline and its analogs. The hallucinogenic potency of mescaline is increased by α-methylation and by homologation of the 4-methoxy group but it not clear whether these structural modifications have similar effects on the activity of mescaline in rodent models.

Methods: In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of mescaline and several analogs in C57BL/6J mice. HTR experiments were conducted with mescaline, escaline (4-ethoxy-3,5-dimethoxyphenylethylamine) and proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), their α-methyl homologs TMA (3,4,5-trimethoxyamphetamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine) and 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and the 2,4,5-substituted regioisomers TMA-2 (2,4,5-trimethoxyamphetamine), MEM (4-ethoxy-2,5-dimethoxyamphetamine) and MPM (2,5-dimethoxy-4-propoxyamphetamine).

Results: TMA induced the HTR and was twice as potent as mescaline. For both mescaline and TMA, replacing the 4-methoxy substituent with an ethoxy or propoxy group increased potency in the HTR assay. By contrast, although TMA-2 also induced the HTR with twice the potency of mescaline, potency was not altered by homologation of the 4-alkoxy group in TMA-2.

Conclusions: The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. These findings are consistent with evidence that 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens exhibit distinct structure-activity relationships. These results provide additional evidence that the HTR assay can be used to investigate the structure-activity relationships of serotonergic hallucinogens.

Keywords: Psychedelic; animal model; head shake; phenylethylamine; phenylisopropylamine.

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Conflict of interest statement

Declaration of Conflicting Interests

The Authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
Chemical structures of the hallucinogens tested in these studies. The typical dose ranges used in humans are indicated (data from: Shulgin and Shulgin, 1991; Shulgin, 1978).
Figure 2.
Figure 2.
Time-course of the head twitch response induced by mescaline (A) and its 4-position homologs escaline (B) and proscaline (C). Data are presented as group means in 2-min blocks.
Figure 3.
Figure 3.
Time-course of the head twitch response induced by TMA (A) and its 4-position homologs 3C-E (B) and 3C-P (C). Data are presented as group means in 2-min blocks.
Figure 4.
Figure 4.
Time-course of the head twitch response induced by TMA-2 (A) and its 4-position homologs MEM (B) and MPM (C). Data are presented as group means in 2-min blocks.
See this image and copyright information in PMC

References

    1. Barfknecht CF and Nichols DE. (1975) Correlation of psychotomimetic activity of phenethylamines and amphetamines with 1-octanol-water partition coefficients. J Med Chem 18: 208–210. - PubMed
    1. Blough BE, Landavazo A, Decker AM, et al. (2014) Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes. Psychopharmacology (Berl) 231: 4135–4144. - PMC - PubMed
    1. Brandt SD, Kavanagh PV, Westphal F, et al. (2017a) Return of the lysergamides. Part II: Analytical and behavioural characterization of N6 -allyl-6-norlysergic acid diethylamide (AL-LAD) and (2’S,4’S)-lysergic acid 2,4-dimethylazetidide (LSZ). Drug Test Anal 9: 38–50. - PMC - PubMed
    1. Brandt SD, Kavanagh PV, Westphal F, et al. (2017b) Return of the lysergamides. Part III: Analytical characterization of N(6) -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1-propionyl ETH-LAD (1P-ETH-LAD). Drug Test Anal 9: 1641–1649. - PMC - PubMed
    1. Brandt SD, Kavanagh PV, Westphal F, et al. (2016) Return of the lysergamides. Part I: Analytical and behavioural characterization of 1-propionyl-d-lysergic acid diethylamide (1P-LSD). Drug Test Anal 8: 891–902. - PMC - PubMed

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