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. 2019 Jun;369(3):328-336.
doi: 10.1124/jpet.118.255976. Epub 2019 Mar 21.

The Supplement Adulterant β-Methylphenethylamine Increases Blood Pressure by Acting at Peripheral Norepinephrine Transporters

Charles W Schindler  1 , Eric B Thorndike  2 , Kenner C Rice  2 , John S Partilla  2 , Michael H Baumann  2
Affiliations

The Supplement Adulterant β-Methylphenethylamine Increases Blood Pressure by Acting at Peripheral Norepinephrine Transporters

Charles W Schindler et al. J Pharmacol Exp Ther. 2019 Jun.

Abstract

β-Methylphenethylamine [(BMPEA), 2-phenylpropan-1-amine] is a structural isomer of amphetamine (1-phenylpropan-2-amine) that has been identified in preworkout and weight loss supplements, yet little information is available about its pharmacology. Here, the neurochemical and cardiovascular effects of BMPEA and its analogs, N-methyl-2-phenylpropan-1-amine (MPPA) and N,N-dimethyl-2-phenylpropan-1-amine (DMPPA), were compared with structurally related amphetamines. As expected, amphetamine and methamphetamine were potent substrate-type releasing agents at dopamine transporters (DATs) and norepinephrine transporters (NETs) in rat brain synaptosomes. BMPEA and MPPA were also substrates at DATs and NETs, but they were at least 10-fold less potent than amphetamine. DMPPA was a weak substrate only at NETs. Importantly, the releasing actions of BMPEA and MPPA were more potent at NETs than DATs. Amphetamine produced significant dose-related increases in blood pressure (BP), heart rate (HR), and locomotor activity in conscious rats fitted with surgically implanted biotelemetry transmitters. BMPEA, MPPA, and DMPPA produced increases in BP that were similar to the effects of amphetamine, but the compounds failed to substantially affect HR or activity. The hypertensive effect of BMPEA was reversed by the α-adrenergic antagonist prazosin but not the ganglionic blocker chlorisondamine. Radioligand binding at various G protein-coupled receptors did not identify nontransporter sites of action that could account for cardiovascular effects of BMPEA or its analogs. Our results show that BMPEA, MPPA, and DMPPA are biologically active. The compounds are unlikely to be abused due to weak effects at DATs, but they could produce adverse cardiovascular effects via substrate activity at peripheral NET sites.

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Figures

Fig. 1.
Fig. 1.
Chemical structures of amphetamine and BMPEA analogs examined in this study.
Fig. 2.
Fig. 2.
Concentration-response effects for analogs of amphetamine (AMPH) and BMPEA to stimulate [3H]MPP+ efflux (i.e., release) via the DAT (upper panels) or NET (lower panels). Rat brain synaptosomes were preloaded with 9 nM [3H]MPP+, and different concentrations of AMPH, methamphetamine (METH), dimethylamphetamine (DIMETH), BMPEA, MPPA, or DMPPA were added to stimulate release. Results are plotted as a percentage of maximal release elicited by 10 µM tyramine. Data are mean ± S.D. for N = 3 separate experiments performed in triplicate.
Fig. 3.
Fig. 3.
Concentration-response effects for amphetamine (AMPH) and BMPEA to stimulate [3H]MPP+ efflux (i.e., release) in the presence or absence of the DAT blocker GBR12909 [(GBR), upper panels] or the NET blocker desipramine [(DMI), lower panels]. Rat brain synaptosomes were preloaded with 9 nM [3H]MPP+, and different concentrations of AMPH or BMPEA were added to stimulate release in the presence or absence of 1 nM GBR12909 for DAT assays or 8 nM desipramine for NET assays. Data are mean ± S.D. for N = 3 separate experiments performed in triplicate.
Fig. 4.
Fig. 4.
Time-course effects of amphetamine (AMPH) and BMPEA to influence BP (upper panels) and HR (lower panels) in conscious rats bearing biotelemetry transmitters. Rats received subcutaneous injections of AMPH or BMPEA and were subsequently moved to recording chambers for 3-hour test sessions. Mean values for N = 7 rats/group are plotted for 1-minute epochs over the entire 180-minute sampling period.
Fig. 5.
Fig. 5.
Dose-effect functions for amphetamine (AMPH), BMPEA, MPPA, and DMPPA on BP, HR, motor activity, and body temperature. Data are mean values from the first hour of test sessions, where the effects of the test drugs were maximal. Solid symbols indicate significant differences compared with the respective saline control group. Data are mean ± S.E.M. for N = 7 rats/group.
Fig. 6.
Fig. 6.
Effects of pretreatment with the ganglionic blocker chlorisondamine (1 mg/kg, s.c.) or the α1-adrenoreceptor antagonist prazosin (0.3 mg/kg, s.c.) on BP (upper panels) or HR (lower panels) produced by 30 mg/kg BMPEA. Data are mean ± S.E.M. from the first hour of the sessions, where the effects of BMPEA were maximal; N = 5 rats/group. Filled bars represent a significant difference from saline + saline (Sal + Sal); * indicates a significant difference from BMPEA alone [saline (Sal) or vehicle (Veh) + BMPEA 30].
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