PPAP, BPAP and the activity enhancers

Start with what a releaser does, because that is the familiar half. Amphetamine and methamphetamine are carried into the nerve terminal by the same transporter that normally clears dopamine out of the synapse. Once inside they make that transporter run backwards, and they disturb vesicular storage so the cytoplasm fills with free transmitter. Dopamine then leaves the cell down its own gradient. The output no longer has anything to do with whether the neuron fires; a quiet neuron leaks just as well as a busy one. That is why a releaser floods a synapse, and why the effect is felt as being pushed rather than as being more capable.

An activity enhancer, as Knoll defined it, does not do that. The neuron still has to fire. When an action potential arrives at the terminal, slightly more transmitter comes out than would otherwise have come out. No impulse, no effect. Knoll's phrase for it was enhancement of the impulse propagation mediated release of transmitter, which is a mouthful; the plain version is gain control on ordinary firing. The brain decides when and where; the drug adjusts how much.

This distinction is not rhetorical, and that matters. It is two separate numbers in a brain slice experiment. You measure resting release with no stimulation, then measure release under electrical stimulation, and compare. A releaser raises the resting number. An enhancer leaves the resting number alone and raises the stimulated one. When Harsing and colleagues ran methamphetamine and BPAP side by side in rat striatal slices, methamphetamine produced non-vesicular dopamine release and BPAP produced none at all, while potentiating stimulated release of vesicular origin ^[11]. Whatever else is uncertain about this class, the measurement that defines it is a real measurement with a clear negative result attached.

What that would mean in a person is a separate question, and an open one. A releaser sets its own output; an enhancer would scale whatever the brain was already doing, which in principle means no effect on a system that is quiet and a proportionate effect on one that is active. That is an attractive story. It has never been tested in a human being.

Selegiline, originally E-250 and still widely called deprenyl, came out of Knoll's Budapest laboratory in the 1960s and made its name as the first selective inhibitor of monoamine oxidase B. That is the property it is licensed for; it is why it is used in Parkinson's disease and why, as a patch, it is used in depression.

The awkward observation came later. Give rats repeated very small doses of selegiline, far below what is needed for useful MAO-B inhibition, and catecholamine release from discrete brain regions goes up anyway. In Knoll's dose-finding work the threshold was about 0.01 mg/kg for the noradrenergic neurons of the locus coeruleus and 0.025 mg/kg for the dopaminergic neurons of the striatum and substantia nigra ^[3]. The effect did not track enzyme inhibition, and it was not explained by blockade of presynaptic autoreceptors, by uptake inhibition, or by release ^[3]. Something else was happening, and Knoll named it the catecholaminergic activity enhancer effect.

There was an obvious objection, and it is worth stating because it is the reason the rest of this class exists. Selegiline is metabolised to methamphetamine and amphetamine. Both are the levorotatory isomers, which is exactly how a forensic laboratory distinguishes a selegiline patient from a methamphetamine user, since street methamphetamine yields the (+) isomers. The quantities are not trivial: in human volunteers, roughly 40 percent of an administered selegiline dose was recovered in urine within 48 hours as desmethylselegiline plus (-)-methamphetamine and (-)-amphetamine, and the parent drug was not detectable in urine or plasma at all ^[4]. Any claim that selegiline does something amphetamines cannot do therefore has a confound built into the molecule.

The escape route was to build a compound with the enhancer effect and neither of the complications. PPAP, 1-phenyl-2-propylaminopentane, was that compound, described in 1992 as a deprenyl-derived stimulant of a new kind ^[1]. It has no propargylamine group, so it does not inhibit MAO. It is taken up into the catecholaminergic axon terminal and into the vesicular membrane, but it carries nothing out; it has no catecholamine releasing property ^[1]. And it does not break down into amphetamines. Behaviourally it raised motility at 2 mg/kg and only suppressed it at 50 mg/kg, whereas amphetamine's useful window is narrow and closes fast, and it produced substantially less stereotyped behaviour than amphetamine or methamphetamine ^[1]. When PPAP reproduced selegiline's enhancer effect without touching MAO-B, the enhancer effect stopped being an artefact of enzyme inhibition and became a claim in its own right ^[2].

One honest wrinkle, from the group's own data. The stereochemistry of PPAP never settled cleanly. In the 21-day release study the (+) enantiomers of both deprenyl analogues were more active than the (-) forms ^[2]; in the calcium current assay published two years later, (-)-PPAP was much more potent than (+)-PPAP ^[3]. Different assays, same laboratory, opposite answers. BPAP by contrast has a clear active form, the R-(-) enantiomer.

Every member of this class is a 1-aryl-2-propylaminopentane. Take phenethylamine, keep the two-carbon bridge from the aromatic ring to the nitrogen, then hang an n-propyl group on the alpha carbon (which is what makes the chain a pentane) and a second n-propyl on the nitrogen itself. Set that beside amphetamine, which carries a small methyl on the alpha carbon and a free primary amine, and the two propyl groups are the entire difference.

That difference is doing the work. Amphetamine's compact alpha-methyl and unsubstituted amine are what let it behave as a transporter substrate, which is the prerequisite for reverse transport and for releasing. Load both positions with propyl chains and the molecule is still recognised by the terminal, since radiolabelled PPAP accumulates in catecholaminergic axon terminals, but it no longer functions as a substrate that can be carried back out with transmitter in tow ^[1]. The practical consequence is that PPAP became an inhibitor of uptake by obstruction: it blocks the uptake of catecholamines and of releasing agents such as tyramine, simply by occupying the carrier without being ferried through it ^[1].

The second variable is the aromatic ring, and this is where the class splits in two. Aiming for something far more potent than selegiline, Yoneda and colleagues prepared a series of 1-aryl-2-alkylaminoalkanes deliberately unrelated to phenethylamine and the amphetamines, and out of 65 new compounds selected one: (-)-1-(benzofuran-2-yl)-2-propylaminopentane, BPAP ^{[5] [6]}. Swapping phenyl for benzofuran-2-yl turns a phenethylamine-shaped molecule into a tryptamine-shaped one, and the pharmacology follows the shape. PPAP tracks phenylethylamine and reaches catecholamines. BPAP tracks tryptamine and reaches serotonin as well as dopamine and noradrenaline ^[5].

The group tested that split rather than merely asserting it. A close analogue, 3-F-BPAP, antagonised the enhancer effect of BPAP in the shuttle box while leaving the effects of selegiline and PPAP completely unchanged ^[8]. If a single shared site were responsible, blocking BPAP should have blocked the others too. That is the best available evidence that the phenethylamine branch and the tryptamine branch of this class are not the same thing wearing different rings.

The potency gap is large. BPAP raised impulse-evoked release from isolated rat brain stem at 0.18 micromol/L for noradrenaline and dopamine and at 36 nmol/L for serotonin, and from freshly excised discrete brain regions at concentrations between 1 picomolar and 10 femtomolar. In a live rat a single subcutaneous dose of 0.1 microgram per kilogram was enough, and in the shuttle box it was roughly 130 times more potent than selegiline ^[5]. Those are not typographical errors; the claimed working concentrations really are that low, and that is itself a reason for caution, since effects at femtomolar concentrations are notoriously hard for other laboratories to reproduce.

MPAP, 1-(3,4-methylenedioxyphenyl)-2-propylaminopentane, sits between the two branches: a methylenedioxy ring in place of plain phenyl. It comes from the same structure-activity series ^[6] and is reported as roughly five times more potent than PPAP in rodent behavioural tests, and unlike PPAP it reaches serotonin. That is essentially the whole record. There is no paper devoted to MPAP, no dose, no toxicology and no binding constants; it exists as a row in a table. Descriptions of MPAP circulating online are almost always inference from BPAP applied to a compound that was never separately studied.

The enhancer effect is reported to follow a bell-shaped concentration-effect curve. It rises to a peak and then falls back as concentration keeps climbing. This is not an occasional finding in this literature; it is how the effect is described throughout, and it is visible in the most recent striatal slice work, where BPAP potentiated both dopamine and GABA release around 0.1 nanomolar and the curves for both bent back down at higher concentrations ^[12].

There are actually two bells reported, at wildly different scales: a narrow one in the femtomolar to picomolar range, called the specific enhancer effect, and a second one in the high micromolar range described as non-specific. Only the first is what anyone means by an activity enhancer.

For a reader the practical consequence is blunt. If the effect exists as described, taking more of it does not produce more of it; past the peak you come back down to where you started. It also means that an animal result obtained at 0.0001 mg/kg tells you nothing whatever about the same compound at 10 mg/kg. The same molecule at a thousand times its enhancer dose is, functionally, a different drug, and the section below shows exactly that happening.

It is worth naming the epistemic problem with bell-shaped curves as well, because it cuts both ways. A narrow window with the effect vanishing on both sides is very hard to falsify: any failure to replicate can be attributed to the wrong dose, and no negative result ever settles anything. That does not make the effect unreal. It does mean the claim needs independent replication more than most, and independent replication is the thing this literature does not have.

For most of its history the enhancer effect had no receptor attached to it. It was defined by exclusion: not MAO inhibition, not autoreceptor blockade, not uptake inhibition, not release ^[3]. Later the vesicular monoamine transporter VMAT2 was proposed as the site, with the bell shape attributed to a compound interacting with two distinct places on the same protein.

TAAR1, the trace amine-associated receptor, entered the story only recently. In 2022 Harsing, Knoll and Miklya proposed that BPAP acts through TAAR1, with separate binding sites for releasers and for enhancers driving different protein kinase C dependent phosphorylation, and reported that BPAP also increased VMAT2 operation ^[11]. A follow-up from the same laboratory showed that EPPTB, a TAAR1 antagonist, blocked selegiline's enhancement of stimulated dopamine release, and that rasagiline, which has no enhancer effect of its own, blocked it too, implying rasagiline may be a TAAR1 antagonist. In 2025 the group explained the bell shape by TAAR1 forming heterodimers with dopamine D2 receptors, so that rising occupancy switches TAAR1 signalling off and D2 signalling on ^[12].

How well supported is that? Stated plainly: there are three papers on TAAR1 and this class, all from one laboratory, all authored by the group that has advocated the enhancer concept for three decades. Their own 2025 abstract describes BPAP as a potential agonist for TAAR1 rather than a demonstrated one ^[12]. No published assay shows BPAP activating TAAR1 directly; there is no cAMP curve, no BRET readout and no binding constant for BPAP at TAAR1 in the indexed literature. The case rests on an antagonist blocking an effect, plus the shape of some curves. TAAR1 is also predominantly an intracellular receptor, which adds a requirement rather than removing one. It is a reasonable hypothesis and it may well be right. Repeating the flat sentence that BPAP is a TAAR1 agonist as settled mechanism goes past what has been shown, and that sentence is now everywhere.

There is a further complication that undercuts the tidy story regardless of receptor. BPAP is not mechanistically clean. Measured against human transporters expressed in HEK293 cells, it inhibited dopamine uptake with an IC50 of 42 nM, noradrenaline uptake at 52 nM and serotonin uptake at 640 nM, and it displaced RTI-55 binding at the dopamine transporter with an IC50 of 16 nM ^[9]. Those are ordinary reuptake-inhibitor numbers at ordinary concentrations. On the reassuring side, the same work found BPAP did not release noradrenaline the way tyramine did, and in fact blocked tyramine-induced release ^[9].

And at whole-milligram doses BPAP stops behaving like an enhancer at all. Between 0.3 and 10 mg/kg it increased locomotor activity in rats dose-dependently, an effect blocked by a dopamine D1 antagonist, and the authors attributed it squarely to BPAP's ability to induce dopamine release ^[7]. So the same molecule is characterised as a non-releasing enhancer at 0.0001 mg/kg and as a dopamine releaser at 1 mg/kg, in papers sharing authors. Both can be true, because dose is doing the work. But it means that whenever someone cites a BPAP result, the dose it was obtained at decides which drug they are actually talking about.

The literature is small enough to count. A PubMed search for propylaminopentane returns about 40 records covering the entire class since 1992, and one of those is unrelated. That is the whole indexed body of work on PPAP, MPAP and BPAP combined, accumulated over three decades.

Nearly all of it comes from two places with an interest in the answer. Knoll's department at Semmelweis University produced the concept, the behavioural work and the release measurements; Fujimoto Pharmaceutical Corporation in Japan produced the chemistry, and its chemists appear as co-authors on the key BPAP papers ^{[5] [6]}. A handful of Japanese academic groups contributed, mostly with a Fujimoto co-author attached ^{[7] [9]}. The nearest thing to genuinely independent work is a 2010 study from Kyushu University reporting that BPAP reduced reinstatement of methamphetamine-seeking in rats ^[10]; that tested a behaviour, not the enhancer mechanism.

So the central claim, that these compounds raise transmitter released per impulse without raising resting release, has never been reproduced by a laboratory with no stake in the concept. It is not contradicted either. It is simply unreplicated, which is a different and less comfortable state than either.

The work is also old and it is in animals. The core neurochemistry was published between 1992 and 2004 in rats, mice and cell culture; the recent papers ^{[11] [12]} are mechanistic reinterpretations from the same lineage rather than new independent confirmation.

On humans there is nothing. No clinical trial of PPAP, MPAP or BPAP has been published, and none is registered on ClinicalTrials.gov. The two papers most often pointed to as human evidence, both arguing that enhancer substances should be tried in major depression, are proposals; they make the case for a trial rather than reporting one. Selegiline is the only member of the family with real human data, and that data concerns MAO-B inhibition in Parkinson's disease and transdermal delivery in depression, not enhancer activity.

The takeaway is not that this is nonsense. A drug that scales normal firing rather than overriding it would be a genuinely different kind of stimulant, and the hypothesis deserved better testing than it received; it is a reasonable candidate for someone to pick up and try to replicate properly. But an interesting under-replicated idea from one laboratory is not an established mechanism, and the confidence with which BPAP in particular is discussed online has no counterpart in the papers. There is no human dose, no human safety data, no toxicology and no information at all about long-term use. These belong under research chemicals, not among nootropics with a track record.