Receptor interaction profiles of 4-alkoxy-2,6-dimethoxyphenethylamines (Ψ derivatives) and related amphetamines

A class of psychedelic compounds called 4-substituted 2,6-dimethoxyphenethylamines and their amphetamine counterparts (Ψ derivatives) were tested for their interactions with monoamine receptors and transporters. These derivatives showed moderate to high affinity and activity at the human 5-HT2A receptor, the primary target for psychedelics, with binding affinities ranging from 8 to 1,600 nM and activation potencies from 32 to 3,400 nM. They acted as partial agonists at this receptor. The phenethylamine derivatives also bound to 5-HT1A and 5-HT2C receptors with moderate affinity, while amphetamine derivatives had weaker affinities. Some Ψ derivatives interacted with TAAR1 and adrenergic receptors. Compared to 2,4,5-trisubstituted derivatives, the 2,4,6-trisubstituted Ψ derivatives were generally less potent at the 5-HT2A receptor but more potent than 3,4,5-trisubstituted derivatives.

Study at a glance

Abstract

Background 4-substituted 2,6-dimethoxyphenethylamines and the corresponding amphetamines (so-called pseudo [Ψ] derivatives) are a hitherto mostly unexplored group of psychedelics. Still, preliminary investigations indicate that these derivatives are promising and potent psychedelics in humans. In this study, we examined the monoamine receptor and transporter interaction properties of several 4-alkyloxy-2,6-dimethoxyphenethylamines and amphetamines with varying structural modifications at the 4-alkyloxy position and compared them to structural analogs with 3,4,5- and 2,4,5-substitution patterns. Methods Binding affinities were assessed at human serotonergic 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors, adrenergic α 1A and α 2A receptors, dopaminergic D 2 receptor, rat and mouse trace-amine associated receptor 1 (TAAR1), and human monoamine transporters. Moreover, the Ψ derivatives were examined for their activation potency at human 5-HT 2A and 5-HT 2B receptors and at human TAAR1. Results The tested derivatives displayed moderate to high affinity and activity at the h5-HT 2A receptor ( K i = 8–1,600 nM; EC 50 = 32–3,400 nM). All derivatives were partial agonists at the receptor (activation efficacy ≤84%). Moreover, the phenethylamine derivatives bound to the h5-HT 1A ( K i = 710–4,440 nM) and h5-HT 2C ( K i = 110–3,500 nM) receptors with moderate affinity, whereas the amphetamine derivatives showed weak h5-HT 1A affinities ( K i ≥ 5,100 nM) and comparably lower h5-HT 2C receptor affinities ( K i = 270–10,000 nM). Within the remaining receptors investigated, some of the Ψ derivatives showed significant interactions with the human (EC 50 ≥ 34 nM), rat ( K i ≥ 1.6 nM), and mouse ( K i ≥ 120 nM) TAAR1, the hα 1A adrenoceptor ( K i ≥ 670 nM) and the hα 2A adrenoceptor ( K i ≥ 280 nM). Conclusion The Ψ derivatives mainly interacted with the 5-HT 2A receptor, the primary target for psychedelics, as well as with the 5-HT 2C receptor. The same 4-alkyloxy modification pattern on the related 2,4,5-trisubstituted derivatives exhibited generally slightly more potent 5-HT 2A receptor binding and activation, whereas 3,4,5-trisubstituted derivatives interacted with lower potency; in humans, 2,4,6-trisubstituted derivatives may thus be less potent compared to their 2,4,5-trisubsititued counterparts but more potent compared to their 3,4,5-trisubsititued counterparts.