This in vitro study examines 2,5-dimethoxy-4-substituted phenethylamines (PEAs) including 2C-I, 2C-B, 2C-D, and 2C-H analogs, focusing on their receptor interactions. It finds these compounds act as 5-HT2A receptor antagonists, differing in potency based on specific substituents. This suggests their psychostimulant effects may not solely derive from 5-HT2A receptor agonism.
Abstract of 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes
“We recently described that several 2-(2,5-dimethoxy-4-substituted phenyl)ethylamines (PEAs), including 4-I=2C-I, 4-Br=2C-B, and 4-CH3=2C-D analogs, are partial agonists at 5-HT2C receptors, and show low or even negligible intrinsic efficacy at 5-HT2A receptors. These results raised the proposal that these drugs may act as 5-HT2 antagonists.
To test this hypothesis, Xenopus laevis oocytes were microinjected with the rat clones for 5-HT2A or 5-HT2C receptors. The above-mentioned PEAs and its 4-H analog (2C-H) blocked the 5-HT-induced currents at 5-HT2A, but not at the 5-HT2C receptor, revealing 5-HT2 receptor subtype selectivity. The 5-HT2A receptor antagonism required a 2-min preincubation to attain maximum inhibition.
All PEAs tested shifted the 5-HT concentration–response curves to the right and downward. Their potencies varied with the nature of the C(4) substituent; the relative rank order of their 5-HT2A receptor antagonist potency was 2C-I>2C-B>2C-D>2C-H.
The present results demonstrate that in X. laevis oocytes, a series of 2,5-dimethoxy-4-substituted PEAs blocked the 5-HT2A but not the 5-HT2C receptor-mediated responses. As an alternative hypothesis, we suggest that the psychostimulant activity of the PEAs may not be exclusively associated with partial or full 5-HT2A receptor agonism.”
Authors: Claudio A. Villalobos, Paulina Bull, Patricio Sáez, Bruce K. Cassels & J. Pablo Huidobro-Toro
Summary of 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes
There is abundant evidence that psychostimulants of the indolylalkylamine and phenylethylamine families require the activation of central 5-HT2 receptors. 2C-B, a popular and recreational psychostimulant phenylethylamine, may also exert its psychotropic actions through the activation of 5-HT2A/2C receptors.
Although this new experimental model has limitations, the study demonstrated that the PIAs are generally full 5-HT2C receptor agonists and partial agonists at the 5-HT2A receptor, and that the PEAs are less efficacious agonists, some of them with low or negligible efficacy at the 5-HT2A receptor subtype.
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https://doi.org/10.1038/sj.bjp.0705722
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Villalobos, C. A., Bull, P., Sáez, P., Cassels, B. K., & Huidobro‐Toro, J. P. (2004). 4‐Bromo‐2, 5‐dimethoxyphenethylamine (2C‐B) and structurally related phenylethylamines are potent 5‐HT2A receptor antagonists in Xenopus laevis oocytes. British journal of pharmacology, 141(7), 1167-1174.
Study details
Compounds studied
2C-X
Topics studied
Chemistry
Neuroscience
Safety
Study characteristics
Animal Study
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