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

Abstract

b-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 a-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.

Amphetamine-like Neurochemical and Cardiovascular Effects of α-Ethylphenethylamine Analogs Found in Dietary Supplements

“…*Ki values for the following receptors were >10,000 nM for all 4 drugs tested: Serotonin receptors 5-HT1B, 5-HT1D, 5-HT1E, 5-HT2A, 5-HT2C, 5-HT3, 5-HT5A, 5-HT6, 5HT7 and SERT; Norepinephrine receptors Alpha1A, Alpha1B, Alpha1D, Beta1, Beta2 and Beta3; Dopamine D1, D2, D3, D4 and D5; Histamine receptors H2, H3, H4; Opioid receptors Mu, Kappa, Delta; Muscarinic receptors M1, M2, M3, M4, M5; and Sigma 1, PBR, BZP. The results for amphetamine (AMPH) were reported previously (Schindler et al, 2019).…”

“…In a previous study ( Schindler et al, 2019 ), we examined the pharmacological effects of a PEA analog in which the α -methyl group of amphetamine was moved to the β -position to form BMPEA. This change reduced the potency of BMPEA to increase BP about 30-fold when compared with amphetamine, and at the doses tested, BMPEA did not increase HR or activity.…”

“…Likewise, previous work with other psychomotor stimulants has shown that central or peripheral noradrenergic systems are primarily responsible for their cardiovascular effects. For example, increases in BP produced by BMPEA were blocked by the α -adrenergic antagonist prazosin ( Schindler et al, 2019 ). β -Adrenergic antagonists can block the HR-increasing effects of psychomotor stimulants, including some amphetamines ( Schindler et al, 1992b , 2014 ), cathinones ( Varner et al, 2013 ; Alsufyani and Docherty, 2015 ; Schindler et al, 2016 ), and cocaine ( Branch and Knuepfer, 1992 ; Schindler et al, 1992a ).…”

“…Rats were 2–9 months of age over the course of the experiment. Rats for this study had been previously exposed to BMPEA, prazosin, and chlorisondamine but were allowed at least 3 weeks of washout prior to testing ( Schindler et al, 2019 ).…”

“…Nutritional supplements often contain ingredients that are not listed on the product labels, including analogs of phenethylamine (PEA) that display structural similarity to amphetamine ( Eichner, 2014 ; Pawar and Grundel, 2017 ). We recently showed that the supplement additive β -methylphenethylamine (BMPEA), a positional isomer of amphetamine (i.e., α -methylphenethylamine), increases blood pressure (BP) in rats and may therefore produce adverse effects in humans ( Schindler et al, 2019 ). Another PEA analog previously found in dietary supplements is N , α -diethylphenethylamine (DEPEA; see Fig.…”