Novel psychoactive benzofurans strongly increase extracellular serotonin level in mouse corpus striatum

Abstract

-We examined the effects of three benzofurans [1-(Benzofuran-5-yl)-N-methylpropan-2 -amine (5-MAPB), 1-(Benzofuran-2-yl)-N-methylpropan-2-amine (2-MAPB), and 1-(Benzofuran-5-yl)-N-ethylpropan-2-amine (5-EAPB)] on the extracellular monoamine level in mouse corpus striatum by the microdialysis method and compared them with the effects of psychoactive 3,4-Methylenedioxymethamphetamine (MDMA). The effects of benzofurans on the extracellular monoamine level were qualitatively analogous to that of MDMA, with an increase in serotonin (5-HT) level exceeding dopamine (DA) level. The effects of 2-MAPB and 5-EAPB were almost the same as the effect of MDMA. However, 5-MAPB strongly increased extracellular monoamine level than MDMA. These differences in the potency appear to have a structure-activity relationship. The administration of 5-MAPB (1.6 × 10 -4 mol/kg B.W.) resulted in the death of two-thirds of the mice. The same dose of MDMA did not cause any deaths. The administration of 5-MAPB (1.6 × 10 -4 mol/kg B.W.) produced a 3.41°C ± 0.28°C rise in rectal temperature after 1 hr, whereas the administration of MDMA (1.6 × 10 -4 mol/kg B.W.) produced an approximate 1.85°C ± 0.26°C rise. These results suggest that benzofurans have 5-HT toxicity similar to MDMA, and 5-MAPB has a higher risk of lethal intoxication than MDMA. Furthermore, 5-APB, the metabolic product of 5-MAPB demethylation, may be involved in the acute 5-HT toxicity and may cause lethal intoxication in mice.

Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine

“…Both 6-APDB and 5-APB produce robust and long-lasting locomotor stimulation with roughly equal potency in a manner similar to cocaine, methamphetamine, and several synthetic cathinones (Gatch et al, 2013); however, these benzofurans demonstrate a delayed onset of effects relative to other psychostimulants. The onset of locomotor stimulation induced by 5-APB corresponds to the time-course of monoamine release, as previous reports have indicated robust increases in dopamine and 5-HT 20–40 minutes post-administration in mice, which remain elevated up to 3 hours post-administration (Fuwa et al, 2016). The dose-response pattern and time-course of locomotor stimulation is very similar between these compounds, but 5-APB produces a larger amount of locomotor stimulation at 10 mg/kg than 6-APDB.…”

Benzo fury: A new trend in the drug misuse scene

“…At the highest dose tested, 1.6 × 10 −4 mol/kg body weight, 5‐MAPB induced a notable gradual increase in 5‐HT levels, which did not subside until 180 minutes after the trial; this same dose caused a rise of 3.41 ± 0.28°C in the core temperature of the animals. In comparison, 1.6 × 10 −4 mol/kg of MDMA induced a much less notorious elevation of core temperature (Fuwa et al, ). Hyperthermia is a well‐documented life‐threatening consequence of MDMA abuse that increases all the toxicological manifestations of the drug (da Silva, Silva, & Carmo, ).…”

“…5‐MAPB and 5‐EAPB have an analogous effect to MDMA by promoting higher increases of the levels of serotonin (5‐HT) in the mouse corpus striatum, as compared to dopamine (DA), with the effects of 5‐MAPB even surpassing those observed for MDMA (Fuwa et al, ). In a similar fashion to MDMA, the congeners 6‐APB, 5‐APB, 5‐MAPDB, 5‐EAPB, 5‐APDB and 6‐APDB act primarily as potent monoamine transporter inhibitors, and are capable of inducing monoamine release and of interacting with the trace amine‐associated receptor 1, which is thought to be responsible for the locomotion and the neurochemical stimulant effects of these drugs (Rickli, Kopf, Hoener, & Liechti, ).…”

“…The same authors compared the cytotoxic potential of benzofurans to the classic amphetamine MDMA and determined their greater cytotoxicity, in what concerns the supra‐mentioned endpoints. Another recent work used microdialysis to evaluate the effect of the analogue 5‐MAPB on the levels of extracellular monoamines in the corpus striatum of mice (Fuwa et al, ). A dose‐related response was assessed for 5‐MAPB and its MDMA counterpart, leading to the conclusion that the same dose of the benzofuran can elicit higher toxicity than this amphetamine.…”

Cytotoxic effects of psychotropic benzofuran derivatives,N-methyl-5-(2-aminopropyl)benzofuran and itsN-demethylated derivative, on isolated rat hepatocytes

“…These compounds similarly inhibit three monoamine (dopamine, norepinephrine and serotonin) transporters and release serotonin and norepinephrine (Iversen et al ., ; Rickli et al ., ). Extracellular levels of the three monoamines, particularly serotonin, rapidly increase in the corpus striatum of mice after the oral administration of benzofuran analogues such as 5‐MAPB and 5‐APB (Fuwa et al ., ). It is generally recognized that addiction to such drugs with long‐term repetitious use may have serious adverse effects on the body including mental activity.…”