BPAP

BPAP is PPAP with its phenyl ring replaced by a benzofuran. Joseph Knoll's group in Budapest, which had made selegiline and then PPAP, worked with Fujimoto Pharmaceutical in Japan to change PPAP's aromatic ring. Of 65 new compounds they picked the benzofuran analog, both as a candidate to follow selegiline into the clinic and as a reference compound for studying what they called the catecholaminergic and serotonergic activity enhancer mechanism [1][6]. The compound studied is the (−) enantiomer, whose R configuration was confirmed by X-ray crystallography [7]; Fujimoto's code for it is FPFS-1169 [8]. The group calls it tryptamine-derived, because the program began after they found that tryptamine, the indole analog of phenylethylamine, is itself an enhancer [1].

The founding paper, published in 1999, described a compound active at extraordinarily low concentrations. Brain regions taken from rats injected with 0.1 µg/kg released more dopamine, norepinephrine and serotonin than tissue from saline-treated rats, and freshly excised tissue responded to BPAP in the bath down to 10⁻¹⁴ M. In the shuttle box, where rats given tetrabenazine fail to learn an avoidance task, 0.05 mg/kg restored learning, against 2.5 mg/kg of (−)-PPAP and 5 mg/kg of selegiline; allowing for molecular weight, the authors put BPAP at about 130 times selegiline's potency and called selegiline and PPAP "relatively weak" enhancers by comparison [1]. Unlike selegiline, BPAP does not inhibit MAO-B and is structurally unrelated to the amphetamines; it is a weak MAO-A inhibitor [1].

The early behavioral work came from Fujimoto's own laboratories. BPAP raised locomotor activity in rats at 0.3–10 mg/kg, an effect reduced by a D1 receptor antagonist; it reversed the immobility and drooping eyelids caused by reserpine, where apomorphine and amantadine did not help the eyelids; and it made rats with a one-sided dopamine lesion turn toward the lesion, a sign of release from surviving dopamine terminals [9]. It also let a sub-threshold dose of L-DOPA restore activity in reserpine-treated rats, and it failed when new catecholamine synthesis was blocked as well [10]. Fujimoto described it as a candidate for early Parkinson's disease [3].

Two groups outside Budapest tested it on behavior. At Nagoya University, with a Fujimoto co-author, a single dose reduced immobility in the mouse forced swimming test but repeated dosing did not, while repeated dosing, and not a single dose, restored social interaction in mice stressed by forced swimming; in rats with the olfactory bulbs removed, a model of depression, repeated BPAP restored social interaction, prepulse inhibition and fear learning, and tended to improve sexual function where imipramine did not [11]. At Kyushu University, with no developer among the authors, BPAP reduced cue- and drug-primed relapse to methamphetamine seeking in rats, whether given repeatedly during extinction or once on the test day, without itself reinstating drug seeking or changing methamphetamine self-administration [12].

Later work turned to aging. In a 2016 longevity study, male Wistar rats given 0.1 or 50 µg/kg three times a week from 10 weeks of age lived significantly longer than saline-treated rats, BPAP did better than selegiline, and at 18 months the low-dose rats learned as well as 3-month-old controls [4]. A 2017 report from the same work counted a spontaneous fibromyxosarcoma in 20 of 40 saline-treated rats against 8 and 7 of 40 in the two BPAP groups [13], and a pathology group at the same university, with Knoll and Miklya as co-authors, then found that both doses slowed the growth of transplanted lung adenocarcinoma in mice [14]. The test that did not agree came in 2024, from a behavioral pharmacology group in the same department: 15 aged, food-restricted rats trained on four cognitive tasks received BPAP on weekdays from 27 months of age until death, and neither their cognition nor their lifespan differed from 15 saline-treated rats [5].

The literature has no human data at all. Knoll proposed lifelong daily BPAP in 2001 [15], the 2017 paper suggested testing it in people against the spread of cancer [13], and the developers' reviews describe it as a promising treatment for depression, Parkinson's disease and Alzheimer's disease [16][17], but no trial, case report or human pharmacokinetic study was found. Most of the papers have Knoll, his successor Ildikó Miklya or Fujimoto staff among the authors, and the recent ones say Fujimoto supplied the compound or funded the work [2][5]. Many of the papers are in Elsevier journals and were read for this page from their abstracts; the 1999 founding paper, the 2005 midbrain-slice paper, the 2022 and 2025 receptor papers, the lung-cancer paper and the 2024 aging study were read in full.

The enhancer effect is measured on stimulated release. In Knoll's assays a nerve preparation is loaded with labeled transmitter and stimulated electrically, and an "enhancer" raises the amount released by each burst without changing what leaks out between bursts. BPAP did this for norepinephrine and dopamine at 0.18 µM and for serotonin at 36 nM in isolated rat brain stem [1]. Desipramine, fluoxetine, clorgyline, lazabemide and the dopamine agonists pergolide and bromocriptine did not, which the group took as evidence that the effect is not reuptake or MAO inhibition or receptor stimulation [18]. The 2022 and 2025 papers repeated the finding in rat striatal slices: BPAP raised stimulated dopamine release and left resting release untouched at every concentration from 10⁻¹⁵ to 10⁻⁵ M [2][19]. Methamphetamine, by contrast, raised resting release, which is what makes it a releaser [2].

The dose curves are bell-shaped, twice over. Effects appear in a low window and a high one, with nothing in between. Norepinephrine release from the locus coeruleus rose from 10⁻¹⁶ M, peaked at 10⁻¹³ M, vanished at 10⁻¹⁰ M, and returned between 10⁻⁸ and 10⁻⁶ M before vanishing again at 10⁻⁵ M; in living rats, 0.5 µg/kg raised it from 4.7 to 15.4 nmol/g while 50 µg/kg did nothing [20]. The developers proposed high- and low-affinity "enhancer receptors" and suggested they might be the trace amine receptors cloned shortly before [20].

A receptor has been proposed: TAAR1. Trace amine-associated receptor 1 is an intracellular receptor for phenylethylamine, tyramine and the amphetamines. In striatal slices the TAAR1 antagonist EPPTB abolished BPAP's effect on stimulated dopamine release, as did blocking protein kinase C, and the DAT blocker nomifensine also abolished it, which the authors read as BPAP entering the nerve ending through the dopamine transporter before acting on TAAR1 inside [2]. They propose that TAAR1 has one site for releasers with small groups on the nitrogen and α-carbon and another for enhancers with bulky propyl groups, such as PPAP and BPAP, and that BPAP also strengthens VMAT2, the pump that fills vesicles [2]. The 2025 paper suggested that the falling half of each bell curve comes from TAAR1 pairing with dopamine D2 receptors and switching its own signal off [19]. The papers read for this page report no binding assay and no study in cells engineered to express TAAR1, and an earlier paper from the same group had named VMAT2 itself as the main site of action [13].

It is also a potent reuptake inhibitor. The 1999 paper said BPAP does not inhibit the plasma membrane transporter [1]. A 2003 Fujimoto study, supported by the US National Institute on Drug Abuse, measured it in cells expressing the human transporters and found the opposite: IC50 values of 42 nM for dopamine uptake and 52 nM for norepinephrine uptake, both more potent than cocaine, and 640 nM for serotonin, weaker than cocaine [3]. These concentrations are far higher than the femtomolar-to-picomolar enhancer window. How much of BPAP's behavioral effect at milligram doses comes from reuptake inhibition rather than "enhancement" has not been settled. Like a reuptake inhibitor, and unlike tyramine, it blocked tyramine-induced norepinephrine release rather than causing release itself [1][3].

It does not work exactly like selegiline. A weak analog, 3-F-BPAP, blocked BPAP's reversal of tetrabenazine in the shuttle box but left the effects of selegiline and PPAP intact, which the developers called the first evidence that the phenylethylamine-derived and tryptamine-derived enhancers act differently [21]. BPAP also acts strongly on serotonin neurons, where selegiline acts mainly on catecholamine neurons [1][16]. BPAP inhibits MAO-A weakly (IC50 0.4 µM in mouse brain) and MAO-B hardly at all (280 µM) [1].

Little else binds. At 10 µM it bound only α2-adrenoceptors among the catecholamine and serotonin receptors screened, and the α2 blocker yohimbine did not mimic it [1]. In the striatum it also raised stimulated GABA release in two windows, an effect the D2 blocker sulpiride abolished [19]. Over three weeks, low doses raised phosphorylated AMPA (GluR1) and NMDA (GluN2B) receptor subunits in the rat prefrontal cortex and lowered night-time corticosterone, and high doses tended to reduce anxiety-like behavior on the elevated plus maze; the paper reports these effects for the low doses of BPAP and selegiline together, and for their high doses together [22]. In chronically stressed rats, a Slovak-Hungarian group found lower GluR1 expression in the prefrontal cortex and no change in stress hormones or anxiety [23].

Protection of cells in culture. BPAP raised the survival of rat hippocampal neurons exposed to β-amyloid from about 20% to 70%, again in two windows peaking at 10⁻¹⁴ and 10⁻⁸ M; the racemate was used [1][6]. It kept cortical neurons alive in serum-free culture through sigma receptors [24], protected human dopaminergic SH-SY5Y cells from an endogenous neurotoxin by stabilizing mitochondria and inducing Bcl-2 [8], and protected human brain endothelial cells and rat PC12 cells after hypoxia [25]. It raised BDNF and its receptor trkB in rat midbrain slice cultures at 10⁻⁹–10⁻⁷ M [26]; in isolated mouse astrocytes it raised NGF, BDNF and GDNF only at micromolar to millimolar concentrations, with no effect in the femtomolar range [27][28].

BPAP has been studied only as the hydrochloride of the R-(−) enantiomer, dissolved in saline [5][10]. The developers published two enantioselective syntheses, one starting from an (R)-aziridine and one from an (R)-norvaline amide, and confirmed the configuration by X-ray crystallography [7]. Some of the earliest experiments used the racemate [6].

No clinical formulation is described in the papers read for this page. The only absorption data come from rats given carbon-14-labeled BPAP, in which radioactivity was well absorbed whether given by mouth, under the skin or into the abdomen, peaked at 30–60 minutes and reached the brain [29]. Because only total radioactivity was measured, those figures cannot separate BPAP from its metabolites.

There is no human safety data. No trial, case report or human pharmacokinetic study was found, and the developers' descriptions of BPAP as safe, well tolerated and of low toxicity [14][16] are not backed by any toxicology study in the papers read for this page: no lethal dose, repeat-dose toxicity, genetic toxicity or cardiovascular data appear.

In animals it has been given for life. Rats received it three times a week from 10 weeks of age until death in the 2016 longevity study and lived longer [4], and aged rats received it on weekdays from 27 months until death in the 2024 study and lived as long as controls [5]. These were not designed as safety studies.

Its pharmacology points to the questions any dopamine and norepinephrine reuptake inhibitor raises. It blocks both transporters more potently than cocaine in cell assays [3] and raised locomotor activity in rats at 0.3 mg/kg and above [9][10]. It did not support methamphetamine self-administration or reinstate drug seeking in rats [12], which is reassuring about abuse liability but is a single rat study. It blocked, rather than caused, tyramine-induced norepinephrine release [3].