Phenylpropylaminopentane

PPAP, also known as α,N-dipropylphenethylamine (DPPEA) or as α-desmethyl-α,N-dipropylamphetamine, is a substituted phenethylamine and amphetamine derivative.^[4] It was derived from structural modification of selegiline (L-deprenyl; (R)-(–)-N,α-dimethyl-N-2-propynylphenethylamine).^[4]

Both racemic 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 in chemical structure to propylamphetamine (N-propylamphetamine; NPA; PAL-424), but has an α-propyl chain instead of an α-methyl group. It is also similar in structure to α-propylphenethylamine (APPEA; PAL-550), but has an N-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-potency dopamine reuptake inhibitors (IC₅₀Tooltip half-maximal inhibitory concentration = 1,013 nM and 2,596 nM, respectively) and are inactive as dopamine releasing agents in vitro.^[19] Another similar analogue of PPAP is N,α-diethylphenethylamine (DEPEA), which is a norepinephrine–dopamine releasing agent and/or reuptake inhibitor.^[20][21][14] A more well-known derivative of APPEA related to PPAP is the cathinone pentedrone (α-propyl-β-keto-N-methylphenethylamine), which is a norepinephrine–dopamine reuptake inhibitor.

A related MAE, BPAP, is a substituted benzofuran derivative and tryptamine relative that was derived from structural modification of PPAP.^[1] It was developed by replacement of the benzene ring in PPAP with a benzofuran 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 an indole ring.^[22][14][15]

PPAP (MK-306) and its (–)-enantiomer (–)-PPAP must not be confused with the sigma receptor ligand R(−)-N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane ((–)-PPAP—same acronym)^[23] or with the cephamycin antibiotic cefoxitin (MK-306—same developmental code name).^[24][25][26]

Racemic PPAP (MK-306) was first described in the scientific 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 was synthesized by József Knoll and colleagues.^[8][4] The potencies of the different enantiomers of PPAP were assessed in 1994.^[16] Subsequent papers have employed (–)-PPAP.^{[1][2][5][18]}

Several patents of PPAP have been published.^[34][35][36]

The development of PPAP was critical in elucidating that the CAE effects of selegiline are unrelated to its monoamine 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 is potent and selective than PPAP and, in contrast to PPAP and selegiline, also enhances serotonin.^{[9][1][2][3][10]}

In 2025, PPAP was found to act as a potent catecholamine reuptake inhibitor.^[6]

PPAP has been proposed as a potential therapeutic agent for attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, and depression based on preclinical findings.^[4] The developers of PPAP attempted to have it clinically studied, but were unsuccessful and it was never assessed in humans.^[1]

• Substituted α-propylphenethylamine
• Methylenedioxyphenylpropylaminopentane (MPAP)
• Naphthylpropylaminopentane (NPAP)