Investigation of the 2,5-dimethoxy motif in phenethylamine Serotonin 2A receptor agonists

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Investigation of the 2,5-dimethoxy motif in phenethylamine Serotonin 2A receptor agonists. / Marcher-Rørsted, Emil; Halberstadt, Adam L; Klein, Adam K; Chatha, Muhammad; Jademyr, Simon; Jensen, Anders A; Kristensen, Jesper L.

In: ACS Chemical Neuroscience, Vol. 11, 2020, p. 1238-1244.

Research output: Contribution to journalLetterResearchpeer-review

Harvard

Marcher-Rørsted, E, Halberstadt, AL, Klein, AK, Chatha, M, Jademyr, S, Jensen, AA & Kristensen, JL 2020, 'Investigation of the 2,5-dimethoxy motif in phenethylamine Serotonin 2A receptor agonists', ACS Chemical Neuroscience, vol. 11, pp. 1238-1244. https://doi.org/10.1021/acschemneuro.0c00129

APA

Marcher-Rørsted, E., Halberstadt, A. L., Klein, A. K., Chatha, M., Jademyr, S., Jensen, A. A., & Kristensen, J. L. (2020). Investigation of the 2,5-dimethoxy motif in phenethylamine Serotonin 2A receptor agonists. ACS Chemical Neuroscience, 11, 1238-1244. https://doi.org/10.1021/acschemneuro.0c00129

Vancouver

Marcher-Rørsted E, Halberstadt AL, Klein AK, Chatha M, Jademyr S, Jensen AA et al. Investigation of the 2,5-dimethoxy motif in phenethylamine Serotonin 2A receptor agonists. ACS Chemical Neuroscience. 2020;11:1238-1244. https://doi.org/10.1021/acschemneuro.0c00129

Author

Marcher-Rørsted, Emil ; Halberstadt, Adam L ; Klein, Adam K ; Chatha, Muhammad ; Jademyr, Simon ; Jensen, Anders A ; Kristensen, Jesper L. / Investigation of the 2,5-dimethoxy motif in phenethylamine Serotonin 2A receptor agonists. In: ACS Chemical Neuroscience. 2020 ; Vol. 11. pp. 1238-1244.

Bibtex

@article{eb384082eef7430bbe15421384b57023,
title = "Investigation of the 2,5-dimethoxy motif in phenethylamine Serotonin 2A receptor agonists",
abstract = "The 2,5-dimethoxyphenethylamine (2, 5-PEA) scaffold is recognized as a motif conferring potent agonist activity at the seroto-nin 2A receptor (5-HT2AR). The 2,5-dimethoxy motif is present in several classical phenethylamine psychedelics such as mesca-line, TMA-2, DOM, DOI, DOB, 2C-B and 2C-I, and it has previously been suggested that this structural motif is essential for 5-HT2AR activation. In the present study we present data that challenges this assumption. The 2- and 5-desmethoxy derivatives of 2C-B and DOB were synthesized and their pharmacological profiles evaluated in vitro at 5-HT2AR and 5-HT2CR in binding and functional assays and in vivo by assessing their induction of Head Twitch Response in mice. Elimination of either the 2- or 5-methoxy leads to a modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR, which was more pro-nounced upon removal of the 5-methoxy. However, this trend was not mirrored in vivo, as removal of either methoxy group resulted in significant reduction in the compounds ability to induce the Head Twitch Response in mice. Thus, the 2,5-dimethoxyphenethylamine motif appears to be important for in vivo potency of phenethylamine 5-HT2AR agonists, but this does not correlate to the relative affinity and potency of the ligands at the recombinant 5-HT2AR.",
author = "Emil Marcher-R{\o}rsted and Halberstadt, {Adam L} and Klein, {Adam K} and Muhammad Chatha and Simon Jademyr and Jensen, {Anders A} and Kristensen, {Jesper L}",
year = "2020",
doi = "10.1021/acschemneuro.0c00129",
language = "English",
volume = "11",
pages = "1238--1244",
journal = "A C S Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",

}

RIS

TY - JOUR

T1 - Investigation of the 2,5-dimethoxy motif in phenethylamine Serotonin 2A receptor agonists

AU - Marcher-Rørsted, Emil

AU - Halberstadt, Adam L

AU - Klein, Adam K

AU - Chatha, Muhammad

AU - Jademyr, Simon

AU - Jensen, Anders A

AU - Kristensen, Jesper L

PY - 2020

Y1 - 2020

N2 - The 2,5-dimethoxyphenethylamine (2, 5-PEA) scaffold is recognized as a motif conferring potent agonist activity at the seroto-nin 2A receptor (5-HT2AR). The 2,5-dimethoxy motif is present in several classical phenethylamine psychedelics such as mesca-line, TMA-2, DOM, DOI, DOB, 2C-B and 2C-I, and it has previously been suggested that this structural motif is essential for 5-HT2AR activation. In the present study we present data that challenges this assumption. The 2- and 5-desmethoxy derivatives of 2C-B and DOB were synthesized and their pharmacological profiles evaluated in vitro at 5-HT2AR and 5-HT2CR in binding and functional assays and in vivo by assessing their induction of Head Twitch Response in mice. Elimination of either the 2- or 5-methoxy leads to a modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR, which was more pro-nounced upon removal of the 5-methoxy. However, this trend was not mirrored in vivo, as removal of either methoxy group resulted in significant reduction in the compounds ability to induce the Head Twitch Response in mice. Thus, the 2,5-dimethoxyphenethylamine motif appears to be important for in vivo potency of phenethylamine 5-HT2AR agonists, but this does not correlate to the relative affinity and potency of the ligands at the recombinant 5-HT2AR.

AB - The 2,5-dimethoxyphenethylamine (2, 5-PEA) scaffold is recognized as a motif conferring potent agonist activity at the seroto-nin 2A receptor (5-HT2AR). The 2,5-dimethoxy motif is present in several classical phenethylamine psychedelics such as mesca-line, TMA-2, DOM, DOI, DOB, 2C-B and 2C-I, and it has previously been suggested that this structural motif is essential for 5-HT2AR activation. In the present study we present data that challenges this assumption. The 2- and 5-desmethoxy derivatives of 2C-B and DOB were synthesized and their pharmacological profiles evaluated in vitro at 5-HT2AR and 5-HT2CR in binding and functional assays and in vivo by assessing their induction of Head Twitch Response in mice. Elimination of either the 2- or 5-methoxy leads to a modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR, which was more pro-nounced upon removal of the 5-methoxy. However, this trend was not mirrored in vivo, as removal of either methoxy group resulted in significant reduction in the compounds ability to induce the Head Twitch Response in mice. Thus, the 2,5-dimethoxyphenethylamine motif appears to be important for in vivo potency of phenethylamine 5-HT2AR agonists, but this does not correlate to the relative affinity and potency of the ligands at the recombinant 5-HT2AR.

U2 - 10.1021/acschemneuro.0c00129

DO - 10.1021/acschemneuro.0c00129

M3 - Letter

C2 - 32212672

VL - 11

SP - 1238

EP - 1244

JO - A C S Chemical Neuroscience

JF - A C S Chemical Neuroscience

SN - 1948-7193

ER -

ID: 238589652