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

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.

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 D₂ 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.

The tested derivatives displayed moderate to high affinity and activity at the h5-HT_2A receptor (K _i = 8-1,600 nM; EC₅₀ = 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 (EC₅₀ ≥ 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).

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.