Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) has shown efficacy as a medication adjunct for treating post-traumatic stress disorder (PTSD). However, MDMA is also used in nonmedical contexts that pose risk for cardiovascular and neurologic complications. It is well established that MDMA exerts its effects by stimulating transporter-mediated release of the monoamines 5-hydroxytryptamine (5-HT), norepinephrine, and dopamine. Current research efforts are aimed at developing MDMA-like monoamine releasers with better efficacy and safety profiles. To this end, we investigated neurochemical and behavioral effects of novel analogs of the designer drug 5-(2-methylaminopropyl)benzofuran (5-MAPB). We used in vitro transporter assays in rat brain synaptosomes to examine transmitter uptake inhibition and releasing properties for enantiomers of 5-(2-methylaminobutyl)benzofuran (5-MABB) and 6-(2-methylaminobutyl)benzofuran (6-MABB) compared with MDMA. We then tested these same compounds in male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg) from saline. In vitro results revealed that S isomers of 5- and 6-MABB are efficacious releasing agents at transporters for 5-HT (SERT), norepinephrine (NET), and dopamine (DAT). By contrast, R isomers are efficacious releasers at SERT and partial releasers at NET but lack releasing activity at DAT. In vivo results showed that all compounds produce dose-dependent increases in MDMA-lever responding and full substitution at the highest dose tested. The diminished NET and DAT releasing activities for R isomers of 5- and 6-MABB are associated with reduced potency for inducing behavioral effects. Collectively, these findings indicate that the aminoalkyl benzofuran scaffold may be a viable template for developing compounds with MDMA-like properties. SIGNIFICANCE STATEMENT: Despite the clinical utility of 3,4-methylenedioxymethamphetamine (MDMA), the drug is associated with certain cardiovascular risks and metabolic side effects. Developing a therapeutic alternative with MDMA-like monoamine releasing activity is of interest. Our in vitro and in vivo findings indicate that the aminoalkyl benzofuran scaffold may be useful for developing compounds with MDMA-like properties.

Fig. 1.

Chemical structures of 5-(2-aminopropyl)benzofuran (5-APB), 6-(2-aminopropyl)benzofuran (6-APB), 5-(2-methylaminopropyl)benzofuran (5-MAPB), 6-(2-methylaminopropyl)benzofuran (6-MAPB), 5-(2-methylaminobutyl)benzofuran (5-MABB), and 6-(2-methylaminobutyl)benzofuran (6-MABB) compared with MDMA. Asterisks indicate the location of the asymmetric chiral alpha-carbon for each molecule.

Fig. 2.

Concentration-response curves for MDMA, R-5-MABB, S-5-MABB, R-6-MABB and S-6-MABB to inhibit [³H]neurotransmitter uptake into rat brain synaptosomes. [³H]dopamine, [³H]norepinephrine, or [³H]5-HT were used to evaluate transmitter uptake via DAT, NET, or SERT, respectively. Data are percentage of control uptake, expressed as mean ± S.E.M. for N = 3 experiments performed in triplicate.

Fig. 3.

Concentration-response curves for MDMA, R-5-MABB, S-5-MABB, R-6-MABB, and S-6-MABB to evoke transporter-mediated release of [³H]substrates from preloaded rat brain synaptosomes. [³H]MPP+ was used as the radiolabeled substrate for DAT and NET, whereas [³H]5-HT was used as the radiolabeled substrate for SERT. Data are percentage of maximal release, expressed as mean ± S.E.M. for N = 3 to 4 experiments performed in triplicate.

Fig. 4.

Dose-response curves for MDMA, R-5-MABB, S-5-MABB, R-6-MABB, and S-6-MABB to engender MDMA-lever responses in male rats. Percent MDMA-lever responses are shown on the left y-axis, whereas response rates are shown on the right y-axis. Data are mean ± S.E.M. for N = 6 rats per group.