Monoamine activity enhancer



Monoamine activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of compounds that enhance the release of monoamine neurotransmitters in the nervous system. Monoamine activity enhancers are distinct from monoamine releasing agents in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate nerve impulse-evoked monoamine release. That is, monoamine activity enhancers increase the quantities of monoamine neurotransmitters released per electrical impulse received.

Monoamine activity enhancers have been shown to significantly enhance dopamine release in the striatum, substantia nigra, and olfactory tubercle; norepinephrine release from the locus coeruleus; and serotonin release from the raphe nucleus in rodent studies. They have a peculiar and characteristic bimodal concentration–response relationship, with two bell-shaped curves of activity across tested concentration ranges.

Endogenous monoamine activity enhancers
Monoamine activity enhancers can possess selectivity for enhancing the release of a certain monoamine over others. For example, the endogenous monoamine activity enhancer phenylethylamine (PEA) is roughly 100times more selective for potentiating dopamine release over serotonin release. The monoamine-potentiating effects of PEA are distinct from its monoamine-releasing properties, which only present at high concentrations. Conversely, another endogenous monoamine activity enhancer, tryptamine, appears to selectively potentiate serotonin release over dopamine release. Besides PEA and tryptamine, tyramine is a catecholaminergic activity enhancer. However, unlike PEA and tryptamine, tyramine is unable to cross the blood–brain barrier.

Monoamine activity enhancing drugs
Selegiline (a phenylethylamine derivative) is used as an antiparkinsonian agent and antidepressant and exhibits catecholaminergic activity enhancer effects independent of its monoamine oxidase inhibition. It has been shown to enhance both impulse-evoked norepinephrine and dopamine release. Selegiline shows a bimodal concentration–response relationship in terms of its activity enhancer actions for dopamine in the striatum.

The psychostimulants amphetamine and methamphetamine (including both dextromethamphetamine and levomethamphetamine) are catecholaminergic activity enhancers like selegiline, but these drugs are also potent monoamine releasing agents and these actions overshadow the former activities.

Phenylpropylaminopentane (PPAP) is a catecholaminergic activity enhancer for norepinephrine and dopamine that was derived from selegiline. In contrast to selegiline, it lacks monoamine oxidase inhibition and hence is much more selective in its actions.

Benzofuranylpropylaminopentane (BPAP) is a monoaminergic activity enhancer for serotonin, norepinephrine, and dopamine that was derived from tryptamine. It is about 130times more potent in its activity enhancer actions than selegiline. Similarly to selegiline, BPAP shows a bimodal concentration–response relationship in its activity enhancer effects, specifically on norepinephrine in the locus coeruleus.

In contrast to selegiline, rasagiline and its metabolite (R)-1-aminoindan do not have monoamine activity enhancer actions. Similarly, SU-11739 (AGN-1133; J-508), the N-methylated analogue of rasagiline, does not have monoamine activity enhancer actions.

Mechanism of action
The mechanism of action of monoamine activity enhancers, for instance the trace amines, may be explained by their shared affinities for the trace amine-associated receptor (TAAR1). In addition, recent findings have suggested that known synthetic monoamine activity enhancers like BPAP and selegiline may exert their effects via TAAR1 activation. This was evidenced by the TAAR1 antagonist EPPTB reversing their monoamine-activity-enhancing effects.

Antagonists
Antagonists of monoamine activity enhancers are known. For example, 3-F-BPAP, a derivative of BPAP, antagonizes the monoamine activity enhancer actions of BPAP. However, it does not antagonize the activity enhancer actions of selegiline or PPAP. EPPTB, a TAAR1 antagonist, has been found to reverse the monoamine activity enhancer actions of both BPAP and selegiline. Likewise, rasagiline has been found to reverse the monoamine activity enhancer actions of selegiline and has been proposed as a possible TAAR1 antagonist.