Psychedelics have been used by humans for millennia for spiritual, ritual, and medical purposes. Recently, an explosion of interest in psychedelics has occurred in numerous fields including medicinal chemistry. Psychedelics act as agonists at the serotonin 5-HT2A receptor. 5-HT2A activation is believed to underlie their psychedelic and therapeutic actions, though much remains unknown about the polypharmacology and functional activities involved in specific pharmacological effects. The N-benzyl-phenethylamines are some of the most potent 5-HT2A receptor ligands known. However, the physical basis of this high potency is unclear. Likewise, selectivity towards 5-HT2A remains a challenge. A series of N-benzyl-phenethylamines were designed to investigate the structure activity relationship (SAR) of N-benzyl-phenethylamines at 5-HT2receptors. The SAR has focused on the role of sterics and electrostatics of the N-benzyl-aryl-ring on 5-HT2Apotency. Binding affinities (Ki) and functional data (Gq-Ca2+ flux and BRET) were determined at 5-HT2A, 5-HT2B and 5-HT2C. Binding affinities at &gt;40 off-target binding sites were also determined. A range of 5-HT2Abinding affinities and functional activities were observed. 5-HT2A binding affinities and functional potency correlated with measures of electron density at the C5’ position of the N-benzyl-phenyl ring estimated using Hammett sigma values, 1H and 13C NMR chemical shifts, and in silico modeling of electrostatic surface potentials (Hirshfeld charges). This SAR was used to design the highest affinity ligand of the series. Results also show functional selectivity for 5-HT2A signaling with simple ring modifications can be achieved. 5-HT2Apotency (Ki and EC50) correlated with potency in the mouse head twitch response assay, a model showing construct and predictive validity for psychedelic activity. In silico modeling identified three key pi-stacking interactions between the N-benzyl ring and aromatic residues Phe339, Phe340 and Trp336 of 5-HT2A. Ongoing experiments are evaluating the significance of these interactions to the high binding affinities and potent functional activation.

Structure activity relationship studies of N-benzyl-phenethylamines at the 5-HT2A receptor: A role of electrostatics in binding and functional potencies

ACS Spring 2022

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