Phenylpropylaminopentane

Phenylpropylaminopentane

Clinical data
Other names	PPAP; (–)-PPAP; (2R)-PPAP; MK-306; α,N-Dipropylphenethylamine; α-Desmethyl-α,N-dipropylamphetamine; 1-Phenyl-2-propylaminopentane; 1-Phenyl-2-propylamino-pentane; 1-Phenyl-2-propyl-aminopentane
Drug class	Catecholaminergic activity enhancer
Legal status
Legal status	UK: Class A
Identifiers
IUPAC name (2R)-1-Phenyl-N-propylpentan-2-amine
CAS Number	784118-64-5^Y
PubChem CID	51529346
ChemSpider	21106218
UNII	UZ3Q3C2Z57
CompTox Dashboard (EPA)	DTXSID201027213
Chemical and physical data
Formula	C14H23N
Molar mass	205.345 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CCCN[C@H](CCC)Cc1ccccc1
InChI InChI=1S/C14H23N/c1-3-8-14(15-11-4-2)12-13-9-6-5-7-10-13/h5-7,9-10,14-15H,3-4,8,11-12H2,1-2H3/t14-/m1/s1 Key:PBENSVGEGPJNFJ-CQSZACIVSA-N

1-Phenyl-2-propylaminopentane (PPAP; developmental code name MK-306) is an experimental drug related to selegiline which acts as a catecholaminergic activity enhancer (CAE).^[1][2][3][4]

PPAP is a CAE and enhances the nerve impulse propagation-mediated release of norepinephrine and dopamine.^[1][3][4][5] It produces psychostimulant-like effects in animals.^[4] The drug is a phenethylamine and amphetamine derivative and was derived from selegiline.^[3][4]

PPAP was first described in the literature in 1988^[6] and in the first major paper in 1992.^[4][7] It led to the development of the improved monoaminergic 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in 1999.^[1][3] PPAP was a reference compound for studying the MAE system for many years.^[1][2][3] However, it was superseded by BPAP, which is more potent, selective, and also enhances serotonin.^{[8][1][2][3][9][10]} There has been interest in PPAP for potential clinical use in humans, including in the treatment of depression, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease.^[4]

Pharmacology

Pharmacodynamics

Catecholaminergic activity enhancer

PPAP is classified as a catecholaminergic activity enhancer (CAE), a drug that stimulates the impulse propagation-mediated release of the catecholamine neurotransmitters norepinephrine and dopamine in the brain.^{[1][2][3][4][5][11]}

Unlike stimulants such as amphetamine, which release a flood of monoamine neurotransmitters in an uncontrolled manner, (–)-PPAP instead only increases the amount of neurotransmitters that get released when a neuron is stimulated by receiving an impulse from a neighboring neuron.^[11][5] Both amphetamine and (–)-PPAP promote the release of monoamines; however, while amphetamine causes neurons to release neurotransmitter stores into the synapse regardless of external input, (–)-PPAP does not influence the pattern of neurotransmitter release and instead releases a larger amount of neurotransmitters than normal.^[11][5]

Recent findings have suggested that known synthetic monoaminergic activity enhancers (MAEs) like PPAP, BPAP, and selegiline may exert their effects via trace amine-associated receptor 1 (TAAR1) agonism.^[12][13] This was evidenced by the TAAR1 antagonist EPPTB reversing the MAE effects of BPAP and selegiline, among other findings.^[12][13] Another compound, rasagiline, has likewise been found to reverse the effects of MAEs, and has been proposed as a possible TAAR1 antagonist.^[13]

The therapeutic index for PPAP in animal models is greater than that of amphetamine while producing comparable improvements in learning, retention, and antidepressant effects.^[4] It has been found to reduce deficits induced by the dopamine depleting agent tetrabenazine in the shuttle box learning test in rats.^[4][14]

PPAP and selegiline are much less potent than BPAP as MAEs.^[3][10] Whereas PPAP and selegiline are active at doses of 1 to 5 mg/kg in 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 BPAP antagonist 3-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 of serotonin.^{[1][10][2][4]}

Other actions

Unlike the related CAE selegiline, (–)-PPAP has no activity as a monoamine oxidase inhibitor.^[8][15]

Chemistry

PPAP, also known as α,N-dipropylphenethylamine 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][14][1][2][5][16]}

PPAP is similar in chemical structure to propylamphetamine (N-propylamphetamine; PAL-424), but has an extended α-alkyl chain. It is also similar in structure to α-propylphenethylamine (PAL-550), but has an extended N-alkyl chain. A more well-known derivative of α-propylphenethylamine is pentedrone (α-propyl-β-keto-N-methylphenethylamine). N-Propylamphetamine and α-propylphenethylamine act as 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.^[17]

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.^[10][18] 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.^[18][12][13]

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 abbreviation)^[19] or with the cephamycin antibiotic cefoxitin (MK-306—same developmental code name).^[20][21][22]

History

Racemic PPAP (MK-306) was first described in the scientific literature in 1988^[6] and a series of papers characterizing it were published in the early 1990s.^{[23][24][25][26][27][28][7][4][29]} The first major paper on the drug was published in 1992.^[4] It was synthesized by József Knoll and colleagues.^[7][4] The potencies of the different enantiomers of PPAP were assessed in 1994.^[14] Subsequent papers have employed (–)-PPAP.^{[1][2][5][16]}

Several patents of PPAP have been published.^[30][31][32]

The development of PPAP was critical in elucidating that the CAE effects of selegiline are unrelated to its monoamine oxidase inhibition.^[8][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.^{[8][1][2][3][9][10]} This MAE is potent and selective than PPAP and, in contrast to PPAP and selegiline, also enhances serotonin.^{[8][1][2][3][9]}

Research

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]

References

1. Knoll J (2001). "Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain". CNS Drug Rev. 7 (3): 317–45. doi:10.1111/j.1527-3458.2001.tb00202.x. PMC 6494119. PMID 11607046. 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.
2. Knoll J (August 2003). "Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives". Neurochem Res. 28 (8): 1275–1297. doi:10.1023/a:1024224311289. PMID 12834268. 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.
3. Gaszner P, Miklya I (January 2006). "Major depression and the synthetic enhancer substances, (-)-deprenyl and R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 30 (1): 5–14. doi:10.1016/j.pnpbp.2005.06.004. PMID 16023777. S2CID 26570703. 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).
4. Knoll J, Knoll B, Török Z, Timár J, Yasar S (1992). "The pharmacology of 1-phenyl-2-propylamino-pentane (PPAP), a deprenyl-derived new spectrum psychostimulant". Archives Internationales de Pharmacodynamie et de Therapie. 316: 5–29. PMID 1356324.
5. Knoll J, Miklya I, Knoll B, Markó R, Kelemen K (February 1996). "(-)Deprenyl and (-)1-phenyl-2-propylaminopentane, [(-)PPAP], act primarily as potent stimulants of action potential-transmitter release coupling in the catecholaminergic neurons". Life Sciences. 58 (10): 817–827. doi:10.1016/0024-3205(96)00014-8. PMID 8602114.
6. Knoll B, Timar J, Knoll J (1988). "Amphetamine-derived potent psychostimulants devoid of biogenic amine releasing properties". Pharmacological Research Communications. 20: 119–120. doi:10.1016/S0031-6989(88)80670-2.
7. Healy D (2000). "The Psychopharmacology of Life and Death. Interview with Joseph Knoll.". The Psychopharmacologists, Vol. III: Interviews. London: Arnold. pp. 81–110. doi:10.4324/9781003058892-3. ISBN 978-0-340-76110-6. 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. [...]
8. Miklya I (November 2016). "The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015)". Mol Psychiatry. 21 (11): 1499–1503. doi:10.1038/mp.2016.127. PMID 27480491. 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
9. Shimazu S, Miklya I (May 2004). "Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives". Prog Neuropsychopharmacol Biol Psychiatry. 28 (3): 421–427. doi:10.1016/j.pnpbp.2003.11.016. PMID 15093948.
10. Knoll J, Yoneda F, Knoll B, Ohde H, Miklya I (December 1999). "(-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain". British Journal of Pharmacology. 128 (8): 1723–1732. doi:10.1038/sj.bjp.0702995. PMC 1571822. PMID 10588928. 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.
11. Bandala C, Cárdenas-Rodríguez N, Mendoza-Torreblanca JG, Contreras-García IJ, Martínez-López V, Cruz-Hernández TR, et al. (February 2023). "Therapeutic Potential of Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants in Neuronal and Non-Neuronal Pathologies". Pharmaceutics. 15 (2): 693. doi:10.3390/pharmaceutics15020693. PMC 9966027. PMID 36840015. 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].
12. Harsing LG, Knoll J, Miklya I (August 2022). "Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum". Int J Mol Sci. 23 (15): 8543. doi:10.3390/ijms23158543. PMC 9369307. PMID 35955676.
13. Harsing LG, Timar J, Miklya I (August 2023). "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". Int J Mol Sci. 24 (17): 13334. doi:10.3390/ijms241713334. PMC 10487936. PMID 37686140.
14. Gyarmati S, Timár J, Barna L, Knoll B, Knoll J (September 1994). "Reversal of shuttle-box deficit by 1-phenyl-2-propylaminopentane (PPAP)". European Neuropsychopharmacology. 4 (3): 298–299. doi:10.1016/0924-977X(94)90109-0.
15. Csaba G, Kovács P, Pállinger E (January–February 2006). "Acute and delayed effect of (-) deprenyl and (-) 1-phenyl-2-propylaminopentane (PPAP) on the serotonin content of peritoneal cells (white blood cells and mast cells)". Cell Biochemistry and Function. 24 (1): 49–53. doi:10.1002/cbf.1183. PMID 15584092. S2CID 11027835.
16. Simon K, Harmat V, Török Z, Böcskei Z, Hermecz I (15 August 1996). "1-Phenyl-2-(propylamino)pentane, a Memory Enhancer". Acta Crystallographica Section C Crystal Structure Communications. 52 (8): 2090–2092. Bibcode:1996AcCrC..52.2090S. doi:10.1107/S0108270196005148.
17. Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026.
18. Yoneda F, Moto T, Sakae M, Ohde H, Knoll B, Miklya I, et al. (May 2001). "Structure-activity studies leading to (-)1-(benzofuran-2-yl)-2-propylaminopentane, ((-)BPAP), a highly potent, selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain". Bioorg Med Chem. 9 (5): 1197–1212. doi:10.1016/s0968-0896(01)00002-5. PMID 11377178.
19. Glennon RA, Battaglia G, Smith JD (November 1990). "(-)PPAP: a new and selective ligand for sigma binding sites". Pharmacol Biochem Behav. 37 (3): 557–559. doi:10.1016/0091-3057(90)90027-f. PMID 1965044.
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22. Christophidis N, Dawborn JK, Vajda FJ (May 1978). "Studies of intravenous cefoxitin (MK306)". Med J Aust. 1 (9): 512–514. doi:10.5694/j.1326-5377.1978.tb112591.x. PMID 672750.
23. Knoll B, Yasar S, Timár J, Knoll J (1990). "A (-) deprenyl-derived new spectrum psychostimulant". Acta Physiol Hung. 75 (Suppl): 173–174. PMID 1973564.
24. Yasar S, Timár J, Knoll B, Knoll J (1990). "Comparison of the dependence capacity of amphetamine, MK-306 and (-)deprenyl". Acta Physiol Hung. 75 (Suppl): 299–300. PMID 2115235.
25. Knoll B, Yasar S, Faragó I, Kovács I, Knoll J (1990). "1-phenyl-2-propyl-aminopentane. HCl (MK-306): A deprenyl-derived new spectrum psychostimulant". European Journal of Pharmacology. 183 (4): 1464–1465. doi:10.1016/0014-2999(90)94608-Z.
26. Knoll B, Yasar S, Farago I, Kovacs I, Knoll J (1990). "1-phenyl-2-propyl-aminopentane.HCl (MK-306): a deprenyl-derived new spectrum psychostimulant". European Journal of Pharmacology. 183 (2): 454–455. doi:10.1016/0014-2999(90)93343-O.
27. Timár J, Yasar S, Knoll B, Knoll J (1990). "Comparison of the effects of (-)deprenyl, 1-phenyl-2-propyl-aminopentane (MK-306) and amphetamine on the striatal and limbic dopaminergic system". Acta Physiol Hung. 75 (Suppl): 279–280. PMID 2115233.
28. Gyarmati S, Hársing LG, Tekes K, Knoll J (1990). "Repeated administration of (-)deprenyl leaves the mesolimbic dopaminergic activity unchanged". Acta Physiol Hung. 75 (Suppl): 133–134. PMID 2115226.
29. Knoll B, Timár J, Knoll J (1992). "Analysis of the mechanism of the action of the psychostimulant effect of 1-phenyl-2-propylaminopentane (PPAP). A comparison with amphetamine". Pharmacological Research. 25: 48–49. doi:10.1016/1043-6618(92)90280-O.
30. US 5220068, Knoll J, Simay A, Szinnyei E, Somfai E, Torok Z, Mozsolits K, Bergmann J, "Psychostimulant agent", issued 15 June 1993, assigned to Chinoin Private Co Ltd. 
31. US 5075338, Knoll J, Simay A, Szinnyei E, Somfai E, Torok Z, Mozsolits K, Bergmann J, "Method of treatment of learning deficiency", issued 24 December 2001, assigned to Chinoin Private Co Ltd. 
32. US 6214859, Yoneda F, Knoll J, Ode H, Sakae M, Katurada M, Moto T, Ando T, Shimazu S, Takahata K, Fujimoto M, "Ethylamine derivatives", issued 10 April 2001, assigned to Fujimoto Brothers Co Ltd.