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 journal › Letter › Research › peer-review
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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 - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
ER -
ID: 238589652