Directional lipophilic character in a series of psychotomimetic phenethylamine derivatives

Nichols, David E.; Shulgin, Alexander T.; Dyer, Donald C.

doi:10.1016/0024-3205(77)90099-6

Cited by 44 publications

(20 citation statements)

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“…The corresponding 3C-O derivatives ( Figure 2 , structures 13-19 ) displayed a comparable 5-HT 2A vs. 5-HT 2C binding preference but did not bind to the 5-HT 1A receptor (section 4.2). The observed moderate 5-HT 2A vs. 5-HT 2C subtype selectivity is in accordance with the many other phenethylamine and amphetamine ligands described by others (Glennon et al, 1980; Glennon et al, 1986; Glennon et al, 1994; Nichols et al, 1994; Nelson et al, 1999; Nichols et al, 2015; Rickli et al, 2015; Nichols, 2016; Rickli et al, 2016; Luethi et al, 2018).…”

Section: Discussionsupporting

confidence: 91%

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: 91%

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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“…According to Barfknecht and Nichols (1975), the optimum lipophilicity for a series of hallucinogenic phenylisopropylamines is log P = 3.14. Mescaline has a relatively low log P value of 0.78, whereas the values for escaline (log P = 1.11) and proscaline (log P = 1.70) are closer to the optimum level (Nichols and Dyer, 1977; Nichols et al, 1977).…”

Section: Discussionmentioning

confidence: 93%

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

et al. 2019

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“…67 A later study identified a steric limitation to the size of the 4-substituent, suggesting that an alkyl group of only about three carbon atoms was tolerated before the activity dropped off. 68 By contrast, polar 4-substituents such as OH, NH 2 , and COOH gave compounds with very low affinity (K i > 25,000 nM). 69 The latter study also examined compounds with very long lipophilic 4-substituents such as n-hexyl and n-octyl, which had high affinities at […”

Section: Ring Substituentsmentioning

confidence: 99%

Structure–activity relationships of serotonin 5‐HT_2A agonists

Nichols

2012

WIREs Membr Transp Signal

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Of the 14 known types of serotonin receptors one of the most extensively studied is the 5-HT 2A (5-hydroxytryptamine) receptor. In the brain, this receptor plays a key role in regulation of cortical function and cognition, appears to be the principal target for the hallucinogenic/psychedelic drugs such as lysergic acid diethylamide (LSD), and also is a target for the newest atypical antipsychotic agents, which are antagonists or inverse agonists at this site. Among the structure-activity relationships that are known for this receptor type, there are three chemical classes of agonists: tryptamines, ergolines, and phenethylamines. Important structural features are identified for agonist activity and some of these agonists have features in common. In addition to effects at the receptor will be the focus, these drugs are also hallucinogenic (psychedelic) agents, and much of the SAR was developed on the basis of effects in humans, before modern pharmacological techniques were available. A certain amount of our knowledge therefore relies on those human studies.

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Directional lipophilic character in a series of psychotomimetic phenethylamine derivatives

Cited by 44 publications

References 7 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

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

Structure–activity relationships of serotonin 5‐HT_2A agonists

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Directional lipophilic character in a series of psychotomimetic phenethylamine derivatives

Cited by 44 publications

References 7 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

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

Structure–activity relationships of serotonin 5‐HT2A agonists

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Structure–activity relationships of serotonin 5‐HT_2A agonists