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

Halberstadt, Adam L.; Chatha, Muhammad; Chapman, Stephen J.; Brandt, Simon D.

doi:10.1177/0269881119826610

Cited by 20 publications

(21 citation statements)

References 73 publications

(114 reference statements)

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“…The moderate selectivity for the 5-HT 2A receptor over 5-HT 1A and 5-HT 2C receptors observed for the 4-alkyloxy substituted derivatives (structures 6 – 8, 12 – 14, 18 – 19 ) is in agreement with previously reported selectivity ratios for various substituted phenethylamines (Barfknecht and Nichols, 1975; Glennon et al, 1983; Pierce and Peroutka, 1989; Glennon et al, 1994; Nichols et al, 1994; Nelson et al, 1999; Rickli et al, 2015; Luethi et al, 2018). However, this selectivity for the 5-HT 2A receptor is not seen for tryptamine psychedelics or LSD, which are non-selective at these serotonergic receptors (Halberstadt and Geyer, 2011; Rickli et al, 2015; Luethi et al, 2018).…”

Section: Discussionsupporting

confidence: 92%

“…On the other hand, significant effects of this modification on the dosage and duration of action in vivo have been observed in humans (Shulgin and Shulgin, 1991). These are thought to be partially caused by an increased metabolic stability (Glennon et al, 1983; Glennon et al, 1992) and increased hydrophobicity (Nichols et al, 1991). Furthermore, intrinsic activity at the receptor also appear to play a significant role (Nichols et al, 1994), as the α-Me group-containing amphetamines show higher intrinsic activity compared to their phenethylamine counterparts (Parrish et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines

Kolaczynska

Luethi

Trachsel³

et al. 2019

Front. Pharmacol.

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Background: 2,4,5-Trimethoxyamphetamine (TMA-2) is a potent psychedelic compound. Structurally related 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and phenethylamine congeners (2C-O derivatives) have been described but their pharmacology is mostly undefined. Therefore, we examined receptor binding and activation profiles of these derivatives at monoamine receptors and transporters. Methods: Receptor binding affinities were determined at the serotonergic 5-HT1A, 5-HT2A, and 5-HT2C receptors, trace amine-associated receptor 1 (TAAR1), adrenergic α1 and α2 receptors, dopaminergic D2 receptor, and at monoamine transporters, using target-transfected cells. Additionally, activation of 5-HT2A and 5-HT2B receptors and TAAR1 was determined. Furthermore, we assessed monoamine transporter inhibition. Results: Both the phenethylamine and amphetamine derivatives (K i = 8–1700 nM and 61–4400 nM, respectively) bound with moderate to high affinities to the 5-HT2A receptor with preference over the 5-HT1A and 5-HT2C receptors (5-HT2A/5-HT1A = 1.4–333 and 5-HT2A/5-HT2C = 2.1–14, respectively). Extending the 4-alkoxy-group generally increased binding affinities at 5-HT2A and 5-HT2C receptors but showed mixed effects in terms of activation potency and efficacy at these receptors. Introduction of a terminal fluorine atom into the 4-ethoxy substituent by trend decreased, and with progressive fluorination increased affinities at the 5-HT2A and 5-HT2C receptors. Little or no effect was observed at the 5-HT1A receptor for any of the substances tested (K i ≥ 2700 nM). Phenethylamines bound more strongly to the TAAR1 (K i = 21–3300 nM) compared with their amphetamine analogs (K i = 630–3100 nM). Conclusion: As seen with earlier series investigated, the 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and phenethylamines share some trends with the many other phenethylamine pharmacophore containing compounds, such as when increasing the size of the 4-substituent and increasing the lipophilicity, the affinities at the 5-HT2A/C subtype also increase, and only weak 5-HT2A/C subtype selectivities were achieved. At least from the binding data available (i.e., high affinity binding at the 5-HT2A receptor) one may predict mainly psychedelic-like effects in humans, at least for some of the compound investigated herein.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines

Kolaczynska

Luethi

Trachsel³

et al. 2019

Front. Pharmacol.

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“…1P‐LSD also showed reduced potency compared to LSD when evaluated in HTR experiments . Generally, the potency relationships for hallucinogens in the mouse HTR paradigm closely parallel the human hallucinogenic data . Interpretation of the HTR potency data, however, is complicated by the possibility that 1B‐LSD serves as a pro‐drug for LSD, as indicated by in vitro assays .…”

Section: Resultsmentioning

confidence: 87%

“…If 1B‐LSD is not the active species and must be hydrolyzed to LSD then extrapolation of mouse potency data to humans is complicated by the possibility of species differences in metabolic enzymes. Nevertheless, although 1B‐LSD is not as potent as LSD in mice, it still has relatively high potency compared to many other hallucinogens …”

Section: Resultsmentioning

confidence: 99%

“…15 Generally, the potency relationships for hallucinogens in the mouse HTR paradigm closely parallel the human hallucinogenic data. 27,30,31 Interpretation of the HTR potency data, however, is complicated by the possibility that 1B-LSD serves as a pro-drug for LSD, as indicated by in vitro assays. 12 If 1B-LSD is not the active species and must be hydrolyzed to LSD then extrapolation of mouse potency data to humans is complicated by the possibility of species differences in metabolic enzymes.…”

Section: Head-twitch Responsementioning

confidence: 99%

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Return of the lysergamides. Part V: Analytical and behavioural characterization of 1‐butanoyl‐d‐lysergic acid diethylamide (1B‐LSD)

Brandt

Kavanagh

Westphal³

et al. 2019

Drug Testing and Analysis

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The psychedelic properties of lysergic acid diethylamide (LSD) have captured the imagination of researchers for many years and its rediscovery as an important research tool is evidenced by its clinical use within neuroscientific and therapeutic settings. At the same time, a number of novel LSD analogs have recently emerged as recreational drugs, which makes it necessary to study their analytical and pharmacological properties. One recent addition to this series of LSD analogs is 1‐butanoyl‐LSD (1B‐LSD), a constitutional isomer of 1‐propanoyl‐6‐ethyl‐6‐nor‐lysergic acid diethylamide (1P‐ETH‐LAD), another LSD analog that was described previously. This study presents a comprehensive analytical characterization of 1B‐LSD employing nuclear magnetic resonance spectroscopy (NMR), low‐ and high‐resolution mass spectrometry platforms, gas‐ and liquid chromatography (GC and LC), and GC‐condensed phase and attenuated total reflection infrared spectroscopy analyses. Analytical differentiation of 1B‐LSD from 1P‐ETH‐LAD was straightforward. LSD and other serotonergic hallucinogens induce the head‐twitch response (HTR) in rats and mice, which is believed to be mediated largely by 5‐HT2A receptor activation. HTR studies were conducted in C57BL/6J mice to assess whether 1B‐LSD has LSD‐like behavioral effects. 1B‐LSD produced a dose‐dependent increase in HTR counts, acting with ~14% (ED50 = 976.7 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). This finding suggests that the behavioral effects of 1B‐LSD are reminiscent of LSD and other serotonergic hallucinogens. The possibility exists that 1B‐LSD serves as a pro‐drug for LSD. Further investigations are warranted to confirm whether 1B‐LSD produces LSD‐like psychoactive effects in humans.

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Automated Detection of Psychedelic-Induced Head-Twitch Response in Mice

Jaster

González-Maeso

2023

Methods in Molecular Biology

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

Abstract: The version presented here may differ from the published version or from the version of the record. Please see the repository URL above for details on accessing the published version and note that access may require a subscription.

Cited by 20 publications

References 73 publications

Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines

Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines

Return of the lysergamides. Part V: Analytical and behavioural characterization of 1‐butanoyl‐d‐lysergic acid diethylamide (1B‐LSD)

Automated Detection of Psychedelic-Induced Head-Twitch Response in Mice

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