 | |
 | |
| Clinical data | |
|---|---|
| Other names | PPAP; (–)-PPAP; (2R)-PPAP; MK-306; α,N-Dipropylphenethylamine; DPPEA; α-Desmethyl-α,N-dipropylamphetamine; 1-Phenyl-2-propylaminopentane; 1-Phenyl-2-propylamino-pentane; 1-Phenyl-2-propyl-aminopentane |
| Drug class | Catecholaminergic activity enhancer;Norepinephrine–dopamine reuptake inhibitor;Stimulant |
| Legal status | |
| Legal status | |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| ChemSpider | |
| UNII | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C14H23N |
| Molar mass | 205.345 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
1-Phenyl-2-propylaminopentane (PPAP), also known asα,N-dipropylphenethylamine (DPPEA) and by the developmental code nameMK-306, is anexperimental drug related toselegiline which acts as acatecholaminergic activity enhancer (CAE).[1][2][3][4]
PPAP is a CAE and enhances thenerve impulse propagation-mediated release ofnorepinephrine anddopamine.[1][3][4][5] It producespsychostimulant-like effects in animals.[4] In 2025, it was discovered that PPAP is apotentcatecholamine reuptake inhibitor, including of dopamine and to a lesser extent of norepinephrine.[6] The drug is aphenethylamine andamphetaminederivative and was derived viastructural modification of selegiline.[3][4]
PPAP was first described in the literature in 1988[7] and in the first major paper in 1992.[4][8] It led to the development of the improvedmonoaminergic activity enhancer (MAE)benzofuranylpropylaminopentane (BPAP) in 1999.[1][3] PPAP was a reference compound for studying the MAE system for many years.[1][2][3] However, it was superseded by BPAP, which is morepotent,selective, and also enhancesserotonin.[9][1][2][3][10][11] There has been interest in PPAP for potential clinical use in humans, including in the treatment ofdepression,attention deficit hyperactivity disorder (ADHD), andAlzheimer's disease.[4] It is acontrolled substance inSweden as of 2020.[12]
PPAP is classified as acatecholaminergic activity enhancer (CAE), a drug that stimulates theimpulse propagation-mediatedrelease of thecatecholamine neurotransmittersnorepinephrine anddopamine in thebrain.[1][2][3][4][5][13]
Unlike stimulants such asamphetamine, which release a flood of monoamine neurotransmitters in an uncontrolled manner, (–)-PPAP instead only increases the amount of neurotransmitters that get released when aneuron is stimulated by receiving an impulse from a neighboring neuron.[13][5] Both amphetamine and (–)-PPAP promote the release of monoamines; however, while amphetamine causes neurons to release neurotransmitter stores into thesynapse regardless of external input, (–)-PPAP does not influence the pattern of neurotransmitter release and instead releases a larger amount of neurotransmitters than normal.[13][5]
Findings in the early 2020s have suggested that knownsyntheticmonoaminergic activity enhancers (MAEs) like PPAP, BPAP, andselegiline may exert their effects viatrace amine-associated receptor 1 (TAAR1)agonism.[14][15] This was evidenced by the TAAR1antagonistEPPTB reversing the MAE effects of BPAP and selegiline, among other findings.[14][15] Another compound,rasagiline, has likewise been found to reverse the effects of MAEs, and has been proposed as a possible TAAR1 antagonist.[15]
Thetherapeutic index for PPAP inanimal models is greater than that of amphetamine while producing comparable improvements inlearning,retention, andantidepressant effects.[4] It has been found to reduce deficits induced by thedopamine depleting agenttetrabenazine in the shuttle box learning test in rats.[4][16]
PPAP and selegiline are much less potent than BPAP as MAEs.[3][11] Whereas PPAP and selegiline are active at doses of 1 to 5 mg/kgin vivo in rats, BPAP is active at doses of 0.05 to 10 mg/kg.[3] BPAP is 130 times as potent as selegiline in the shuttle box test.[1] In contrast to BPAP however, the MAE effects of PPAP and selegiline are not reversed by the BPAPantagonist3-F-BPAP.[2] In addition, whereas PPAP and selegiline are selective as MAEs of norepinephrine and dopamine, BPAP is a MAE of not only norepinephrine and dopamine but also ofserotonin.[1][11][2][4]
PPAP was reported in 2025 to act as apotentcatecholamine reuptake inhibitor, withIC50Tooltip half-maximal inhibitory concentration values of 57.5 nM at thedopamine transporter (DAT), 571 nM at thenorepinephrine transporter (NET), and 19,000 nM at theserotonin transporter (SERT).[6] In terms ofdopamine reuptake inhibition, it was 41-fold less potent thanMDPV but 7-fold more potent thanmephedrone (4-MMC) and 1.3-fold more potent thanamphetamine.[6]
Unlike the related CAEselegiline, (–)-PPAP has no activity as amonoamine oxidase inhibitor.[9][17]
PPAP, also known as α,N-dipropylphenethylamine (DPPEA) or as α-desmethyl-α,N-dipropylamphetamine, is asubstituted phenethylamine andamphetaminederivative.[4] It was derived fromstructural modification ofselegiline (L-deprenyl; (R)-(–)-N,α-dimethyl-N-2-propynylphenethylamine).[4]
Bothracemic PPAP and subsequently its more active (–)- or (2R)-enantiomer (–)-PPAP have been employed in the literature.[4][16][1][2][5][18]
PPAP is similar inchemical structure topropylamphetamine (N-propylamphetamine; NPA; PAL-424), but has an α-propylchain instead of an α-methyl group. It is also similar in structure toα-propylphenethylamine (APPEA; PAL-550), but has anN-propyl chain instead of no substitution. PPAP can be thought of as the combined derivative of NPA and APPEA. NPA and APPEA are known to be low-potencydopamine reuptake inhibitors (IC50Tooltip half-maximal inhibitory concentration = 1,013 nM and 2,596 nM, respectively) and are inactive asdopamine releasing agentsin vitro.[19] Another similar analogue of PPAP isN,α-diethylphenethylamine (DEPEA), which is anorepinephrine–dopamine releasing agent and/orreuptake inhibitor.[20][21][14] A more well-known derivative of APPEA related to PPAP is thecathinonepentedrone (α-propyl-β-keto-N-methylphenethylamine), which is a norepinephrine–dopamine reuptake inhibitor.
A related MAE, BPAP, is asubstituted benzofuran derivative andtryptamine relative that was derived fromstructural modification of PPAP.[1] It was developed by replacement of thebenzenering in PPAP with abenzofuran ring.[11][22] Another related MAE,indolylpropylaminopentane (IPAP), is a tryptamine derivative that is the analogue of PPAP in which the benzene ring has been replaced with anindole ring.[22][14][15]
PPAP (MK-306) and its (–)-enantiomer (–)-PPAP must not be confused with thesigma receptorligandR(−)-N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane ((–)-PPAP—same acronym)[23] or with thecephamycinantibioticcefoxitin (MK-306—same developmental code name).[24][25][26]
Racemic PPAP (MK-306) was first described in thescientific literature in 1988[7] and a series of papers characterizing it were published in the early 1990s.[27][28][29][30][31][32][8][4][33] The first major paper on the drug was published in 1992.[4] It wassynthesized byJózsef Knoll and colleagues.[8][4] Thepotencies of the differentenantiomers of PPAP were assessed in 1994.[16] Subsequent papers have employed (–)-PPAP.[1][2][5][18]
Severalpatents of PPAP have been published.[34][35][36]
The development of PPAP was critical in elucidating that the CAE effects ofselegiline are unrelated to itsmonoamine oxidase inhibition.[9][1][2][3] For many years, PPAP served as a reference compound in studying MAEs.[1][2][3] However, it was eventually superseded by BPAP, which was discovered in 1999.[9][1][2][3][10][11] This MAE ispotent andselective than PPAP and, in contrast to PPAP and selegiline, also enhancesserotonin.[9][1][2][3][10]
In 2025, PPAP was found to act as a potentcatecholamine reuptake inhibitor.[6]
PPAP is acontrolled substance inSweden as of 2020.[12]
PPAP has been proposed as a potential therapeutic agent forattention deficit hyperactivity disorder (ADHD),Alzheimer's disease, anddepression based onpreclinical findings.[4] The developers of PPAP attempted to have it clinically studied, but were unsuccessful and it was never assessed in humans.[1]
Recognizing that (–)deprenyl-induced activation of the nigrostriatal dopaminergic system is unrelated to the inhibition of MAO-B (32), we performed a structure-activity relationship study with the aim of developing deprenyl analogues that, on the one hand, are free of the MAO inhibitory property and, on the other hand, are, in contrast to deprenyl, not metabolized to amphetamines (44). (–)PPAP was selected as a reference substance for further studies. Although (–)PPAP was the first PEA-derived enhancer substance free of the unwanted effects of (–)deprenyl, its clinical efficiency was, in spite of all our efforts, never tested. Figure 8 shows the chemical structure and pharmacologic spectrum of the most important PEA-derived substances that have an enhancer effect.
Because (–)-deprenyl is a highly potent and selective inhibitor of MAO-B, we performed a structure–activity relationship study to develop a deprenyl-derived enhancer substance free of the MAO-B inhibitory property (11). (–)-1-Phenyl-2-propylaminopentane [(–)-PPAP] is our reference substance with this pharmacological profile. [...] Remarkably, 1 mg/kg (–)-PPAP, a (–)-deprenyl–derived enhancer substance devoid of the MAO-B inhibitory potency of its parent compound, fully antagonized tetrabenazine-induced learning depression in HP rats and was ineffective in LP rats. [...] Furthermore, 3-F-BPAP did not influence the enhancer effect of (–)-PPAP, a (–)-deprenyl analogue free of MAO-B inhibitory potency (34, Fig. 4). The data clearly show that the molecular mechanism through which the PEA-derived substances, (–)-deprenyl and (–)-PPAP, exert their enhancer effect in vivo, is not identical with the one through the stimulation of which the tryptamine-derived substance, (–)-BPAP, acts.
This was shown with the development of (–)-1-phenyl-2-propylaminopentane, (–)-PPAP, a derivative of (–)-deprenyl which shared the enhancer activity with its parent compound but was free of its MAO-B inhibitory property (Knoll et al., 1992). (–)-PPAP enhanced dopaminergic activity in the brain like (–)-deprenyl. Knoll's progress in clarifying the mechanism of action of (–)-deprenyl responsible for enhanced dopaminergic activity can be followed in his sequent reviews (Knoll, 1978, 1983, 1987, 1992, 1995), until he came to the final conclusion that (–)-deprenyl acts primarily as a PEA-derived synthetic enhancer substance (Knoll, 1998). [...] Since (–)-deprenyl is a highly potent and selective inhibitor of MAO-B, a structure –activity relationship study was performed to develop a deprenyl-derived enhancer substance being free of the MAO-B inhibitory property (Knoll et al., 1992), and (–)-PPAP is at present the reference substance with this pharmacological profile. [...] The subcutaneous administration of 1 mg/kg tetrabenazine, once daily for 5 days, which depletes the catecholamine stores in the brain, significantly inhibits in rats the acquisition of a two-way conditioned avoidance reflex in the shuttle box. Enhancer substances antagonize, in a dose-dependent manner, the inhibition of learning caused by tetrabenazine. The tryptamine-derived selective and highly potent enhancer, BPAP acted in dose range from 0.05 to 10 mg/kg. The PEA-derived enhancer substances, (–)-deprenyl and (–)-PPAP were much less active (1–5 mg/kg).
This led us in 1992 to 1-Phenyl-2-propylamino-pentane (PPAP) a completely new and very important compound (Fig. 3.1). We started this work in early 1989. I realized finally that we owe the loss of the catecholamine-releasing property, so characteristic of deprenyl, to the bulky substitution attached to the nitrogen, so we put in bulky substitutions to amphetamine. [...]
The demonstration that the DEP analog ( − )-1-phenyl-2- propylaminopentane devoid of MAO inhibitory property, enhanced like DEP the activity of the catecholaminergic brain engine revealed that this effect is unrelated to the selective inhibition of MAO-B. [...] DEVELOPMENT OF (− )-1-PHENYL-2-PROPYLAMINOPENTANE Knoll developed ( − )-1-phenyl-2-propylaminopentane, a DEP analog, which is as equally active with DEP in enhancing the activity of the catecholaminergic brain engine, but it is devoid of MAOI property. This study furnished primary evidence that the main effect of DEP, the specific stimulation of the catecholaminergic brain engine, is unrelated to MAO inhibition.31
Our selected reference compound, (7)BPAP, the benzofuran analogue of (7)PPAP, a much more potent enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain than either (7)deprenyl or (7)PPAP and a compound structurally unrelated to PEA and the amphetamines, seems to be an especially promising experimental tool for studying the nature and the physiological role of the CAE/SAE mechanism in the brain.
DA-releasing agents are a type of drug that induces, through various mechanisms, the release of DA from the presynaptic neuron into the synaptic cleft, leading to an increase in extracellular concentrations of the neurotransmitter. Examples are amphetamine, lisdexamfetamine (L-lysine-d-amphetamine; vyvanse), methamphetamine, methylenedioxymethamphetamine (MDMA), and 4-methylaminorex [27,84–87]. Moreover, (-)1-(benzofuran-2- yl)-2-propylaminopentane, (-)BPAP, (-)-1-phenyl-2-propylaminopentane, and (-)PPAP are enhancers of dopamine activity. BPAP and PPAP act as potent stimulants of neurotransmitter release in dopaminergic neurons, leaving MAO activity largely unchanged. BPAP and PPAP controllably increase the quantity of neurotransmitters that are released when a neuron is stimulated by a neighboring neuron, and they are currently in the research phase [39,88,89].
