Design, Synthesis, and Binding Affinity of Novel N-Naphthyl-Substituted Phenethylamines as 5-HT2AR Agonists

Hundreds of new psychoactive substances (NPS) appear on the legal and illegal drug market each year, with serotonergic phenethylamines, such as 2C-B and derivatives, being some of the most common. Minor, easy-to-perform changes in their chemical structure can drastically change their pharmacology, especially at the 5-HT2A receptor (5-HT2AR). We therefore explored N-naphthyl substitutions on 2C-X/2C-X-Fly scaffolds for their potential enhanced affinity and bias signaling toward β-arrestin. Ten analogues (including five not previously described) were synthesised and characterised by ¹H/¹³C NMR, HPLC, GC-MS, HR-MS, and melting point. Affinity for 5-HT2AR was measured in duplicate competitive [³H]-ketanserin binding assays using transfected CHO-K1 membranes; Ki values were calculated with the Cheng–Prusoff equation. N-naphthylation increased 5-HT2AR affinity by up to ∼600-fold relative to parent compounds. The most potent analogue, 2C-T N-1-Nap, exhibited Ki ≈ 6 nM (pKi = 8.23), comparable to ketanserin. Across the set, 1-naphthyl isomers consistently outperformed their 2-naphthyl counterparts, showing a clear positional effect. Structure–activity analysis suggests a steric clamp in the receptor pocket favoring the 1-orientation. A single N-naphthyl substitution can transform low-potency phenethylamines into high-affinity, potentially β-arrestin-biased 5-HT2AR agonists. While their probable β-arrestin bias necessity further functional assays, it remains unclear how these compounds behave in humans. Nonetheless, they hold great potential for the appearance of non-hallucinogenic psychoplastogens on the drug market.