Structure‐activity Relation of Halogenated 2,5‐Dimethoxyamphetamines Compared to their α‑Desmethyl (2C) Analogues

Abstract

Objective and hypothesis4‐Substituted derivatives of 2,5‐dimethoxyamphetamine (referred to as DOX derivatives) exhibit psychedelic and euphoria‐inducing effects, mainly mediated by 5‐HT2A receptor activation; for this reason, they are used recreationally but also bear therapeutic potential. Studies in humans and animals revealed that 4‐substitution with halogens results in high clinical potency, which increased with increasing size of the halogen. We therefore hypothesized that increasing size of the halogen substituent results in increased affinity at the 5‐HT2A receptor. Hence, we investigated the interaction profiles of 4‐halogenated DOX derivatives with monoaminergic receptors and transporters, and the trace amine‐associated receptor (TAAR) 1 and compared the obtained values to already known data of their α‐desmethyl (2C) analogues. This will lead to a better understanding of the structure‐activity relationship and potential side effects of these compounds, which could lead to novel and more efficacious drug candidates for drug‐assisted psychotherapy.MethodsWe assessed the binding affinity of 2,5‐dimethoxyamphetamine and its halogenated derivatives (DOF, DOC, DOB, and DOI) at several human serotonin (5‐HT) receptor subtypes, adrenergic and dopaminergic receptors, the trace amine‐associated receptor (TAAR) 1, and monoamine transporters. We determined the binding affinity by displacement of radioactively labeled ligands by the DOX derivatives by liquid scintillation counting in cell membrane preparations from cells transfected with the respective human receptor or transporter. Moreover, we investigated the activation potency of the DOX derivatives at the 5‐HT2A and 5‐HT2B receptor by calcium mobilization and at the TAAR1 by cAMP accumulation in cells transfected with the respective human receptor.ResultsThe 5‐HT2A receptor selectivity was substantially increased with increasing size of the halogen, with DOI displaying almost three orders of magnitude higher selectivity towards the 2A receptor subtype than DOF. All tested DOX derivatives were partial to full 5‐HT2A receptor agonists. The observed 5‐HT2 receptor interaction potency of the DOX derivatives is comparable to previously reported values of their 2C analogues, but with increased 5‐HT2A vs. 5‐HT1Aselectivity. None of the tested derivatives showed relevant affinity in the nanomolar range for TAAR1, α1A, α2A, D2, or monoamine transporters.ConclusionThe increased 5‐HT2A vs. 5‐HT1A selectivity of halogenated DOX derivatives compared to their 2C analogues may explain their increased clinical potency. However, increased 5‐HT2A vs. 5‐HT1A selectivity may also increase the risk of seizures. Hence, while DOX derivatives display advantages as 5‐HT2A‐selective compounds for pharmacological research, for clinical applications they may be inferior to 2C derivatives due to their potentially increased risks for seizures.