Evaluation of the Abuse Potential of Novel Amphetamine Derivatives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites

Abstract

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.

Two newly-emerging substituted phenethylamines MAL and BOD induce differential psychopharmacological effects in rodents

“…Moreover, MAL also supported SA at a single dose (0.03 mg/kg) under the FR1 schedule of reinforcement, whereas BOD did not. This is consistent with our previous studies showing that other substituted phenethylamines induce SA in animals (Botanas et al, 2018; Custodio et al, 2017, 2019). Furthermore, our data show that MAL (0.03 mg/kg) was about half-maximal compared to METH, suggesting its modest reinforcing effects.…”

“…Also, MAL (10 mg/kg) increased motor activity during the first and third treatment days as well as on the drug challenge, suggesting it has psychostimulant effects and that it can induce sensitization (Figure 7). This is in line with the psychostimulant effects of substituted phenethylamines after acute or repeated drug administrations and during drug challenge (Botanas et al, 2018; Custodio et al, 2017; Singh et al, 2012). Locomotor sensitization is commonly observed in psychostimulants or abused drugs during acute and/or repeated drug treatments, and on succeeding drug challenges (Robinson and Berridge, 1993; Vanderschuren and Kalivas, 2000; Vezina and Leyton, 2009).…”

25B‐NBOMe, a novel N‐2‐methoxybenzyl‐phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential

“…The SA test was conducted following our previous study, 14 and VEH (n = 10/group) administration. During the injection, a stimulus light was illuminated and remained active for 20 seconds.…”

“…12 The CPP gauges the rewarding value of a drug by measuring the time spent in a drug-paired compartment versus the time spent in a vehicle (VEH)-paired compartment. [13][14][15] Moreover, the SA test assesses the reinforcing effects of a drug by counting the lever responses resulting in drug infusion. 16 Generally, drugs that stimulate the mesolimbic dopamine system induce CPP and/or SA.…”

The potent psychomotor, rewarding and reinforcing properties of 3‐fluoromethamphetamine in rodents

“…After 10 consecutive sessions under FR schedules, the selfadministering rats underwent daily 6 hr self-administration session of PR schedule for 4 consecutive days to assess the reinforcing efficacy of 3-FMA 24. During the PR schedules, the number of lever presses required to obtain a single infusion of 3-FMA was determined by the following equation: responses per drug delivery = [5e (injection number x 0.2) ]-5 (i.e.,1,2,4,6,9,12,15,20,25,32,40,50,62,77, and 95) 48.…”