2-Aminoindan and its Ring-Substituted Derivatives Interact with Plasma Membrane Monoamine Transporters and α2-Adrenergic Receptors

A class of designer drugs derived from 2-aminoindan (2-AI) interacts with monoamine transporters in ways that predict distinct psychoactive effects. 2-AI itself acts as a selective substrate for norepinephrine and dopamine transporters, suggesting (+)-amphetamine-like effects and abuse potential. Adding ring substitutions increases potency at the serotonin transporter while reducing potency at dopamine and norepinephrine transporters. Among the derivatives, MMAI is highly selective for the serotonin transporter, with 100-fold lower potency at norepinephrine and dopamine transporters, while MDAI and 5-MeO-AI show moderate serotonin selectivity. The compounds also bind to α2-adrenoceptor subtypes, with 2-AI having highest affinity for α2C receptors (Ki = 41 nM). Ring-substituted derivatives may produce MDMA-like effects with less abuse liability.

Study at a glance

Abstract

Over the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute. Here, we tested 2-AI and its ring-substituted derivatives 5-MeO-AI, 5-methoxy-6-methyl-2-aminoindan (MMAI), and 5,6-methylenedioxy-2-aminoindan (MDAI) for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We also compared the binding affinities of the aminoindans at 29 receptor and transporter binding sites. 2-AI was a selective substrate for NET and DAT. Ring substitution increased potency at SERT while reducing potency at DAT and NET. MDAI was moderately selective for SERT and NET, with tenfold weaker effects on DAT. 5-MeO-AI exhibited some selectivity for SERT, having sixfold lower potency at NET and 20-fold lower potency at DAT. MMAI was highly selective for SERT, with 100-fold lower potency at NET and DAT. The aminoindans had relatively high affinity for α2-adrenoceptor subtypes. 2-AI had particularly high affinity for α2C receptors (Ki = 41 nM) and slightly lower affinity for the α2A (Ki = 134 nM) and α2B (Ki = 211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT2B receptor. 2-AI is predicted to have (+)-amphetamine-like effects and abuse potential whereas the ring-substituted derivatives may produce 3,4-methylenedioxymethamphetamine (MDMA)-like effects but with less abuse liability.