The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue

Abstract

In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.

Keywords: 3,4-Methylenedioxymethamphetamine (MDMA); 5-(2-Aminopropyl)indole (5-IT); 6-(2-Aminopropyl)indole (6-IT); Locomotor activity; Monoamine releaser; Synthetic stimulants.

Figure 1

Chemical structures of AMT, 5-IT, 6-IT, and MDMA.

Figure 2

Effects of test drugs on release of [³H]MPP⁺ via DAT and NET, and [³H]5-HT via SERT. Data are mean±SD expressed as a % of maximal release response for n=3 experiments performed in triplicate.

Figure 3

Effects of test drugs on cumulative locomotor activity during 90 min sessions, plotted as a function of dose. * represents doses that produced significant increases in beam breaks compared to vehicle. SV stands for saline vehicle and TV stands for tween vehicle.

Figure 4

Time course of locomotor activity, plotted as a function of 10 min bins. Values represent mean±SEM expressed as number of beam breaks for each dose (n=8 per dose). * indicates significant increases in beam breaks compared to vehicle at the same time point. # represents significant attenuation of the effect of the dose compared to its first 10 min bin. The top panel shows data for MDMA, middle panel shows data for 5-IT, and lower panel shows data for 6-IT. For 6-IT, # on the x axis indicates significant attenuation compared to the first 10 min bin for 1.0–5.6 mg/kg, and $ indicates significant attenuation compared to the first 10 min bin for 10.0 mg/kg.