Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of drugs that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release. That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse. MAEs have been shown to significantly enhance nerve impulse-mediated dopamine release in the striatum, substantia nigra, and olfactory tubercle; norepinephrine release from the locus coeruleus; and/or serotonin release from the raphe nucleus in rodent studies. Some MAEs are selective for effects on some of these neurotransmitters but not on others. The maximal impacts of MAEs on brain monoamine levels are more modest than with monoamine releasing agents like amphetamine and monoamine reuptake inhibitors like methylphenidate. MAEs have a peculiar and characteristic bimodal concentration–response relationship, with two bell-shaped curves of MAE activity across tested concentration ranges. Hence, there is a restricted concentration range for optimal pharmacodynamic activity. Endogenous MAEs include certain trace amines like β-phenylethylamine and tryptamine, while synthetic MAEs include certain phenethylamine and tryptamine derivatives like selegiline, phenylpropylaminopentane (PPAP), benzofuranylpropylaminopentane (BPAP), and indolylpropylaminopentane (IPAP). Although this was originally not known, the actions of MAEs may be mediated by agonism of the trace amine-associated receptor 1 (TAAR1). Antagonists of MAEs, like EPPTB (a known TAAR1 antagonist), 3-F-BPAP, and rasagiline, have been identified. In 2025, it was discovered that PPAP is a potent catecholamine reuptake inhibitor, including of dopamine and to a lesser extent of norepinephrine.
Endogenous monoaminergic activity enhancers A few endogenous MAEs have been identified, including the trace amines β-phenylethylamine (PEA), tyramine, and tryptamine. At a concentration of 16 μM (1.6 × 10−5 M), β-phenylethylamine has been shown to act as a MAE for norepinephrine (2.6-fold increase), dopamine (1.3-fold increase), and serotonin (2.3-fold increase) in the rat brainstem in vitro. Conversely, tryptamine has been found to act as a MAE for serotonin (3.6-fold increase) at a concentration of 1.3 μM (1.3 × 10−6 M) and as a MAE for norepinephrine (1.9-fold increase) and dopamine (1.3-fold increase) at a concentration of 13 μΜ (1.3 × 10−5 M) in the rat brainstem in vitro. It is apparent that tryptamine at a concentration of 1.3 μΜ is a much more effective MAE of serotonin than is β-phenylethylamine at a concentration of 16 μM. Hence, tryptamine is a substantially more potent MAE of serotonin than β-phenylethylamine, whereas β-phenylethylamine is a slightly more potent MAE of norepinephrine than tryptamine. It has been suggested that these selectivities may indicate the existence of multiple MAE receptors for these compounds. Tyramine has been shown to act as a MAE of norepinephrine, dopamine, and serotonin in the rat brainstem in vitro similarly to β-phenylethylamine. β-Phenylethylamine and tyramine additionally act as potent monoamine releasing agents of norepinephrine and dopamine at higher concentrations. The MAE and monoamine releasing agent actions of these compounds are mechanistically distinct and they have been referred to as "mixed-acting" monoaminergic potentiators. The synthetic MAE benzofuranylpropylaminopentane (BPAP) has been found to be far more potent as a MAE and to exert MAE and related effects at much lower concentrations than known endogenous MAEs like β-phenylethylamine and tryptamine. For example, BPAP has been found to have peak effects at a concentration of 10−14 M (femtomolar to picomolar range). It has been hypothesized that the very high potency of BPAP may foreshadow the existence of much more potent endogenous MAEs than currently known compounds like β-phenylethylamine and tryptamine that have yet to be identified and may be the true key endogenous mediators for this system.
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