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Phenylpropylaminopentane
Stimulant drug of the substituted phenethylamine class From Wikipedia, the free encyclopedia
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1-Phenyl-2-propylaminopentane (PPAP), also known as α,N-dipropylphenethylamine (DPPEA) and by the 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in 1999.[1][3] PPAP was a reference compound for studying the MAE system for many years.[1][2][3] However, it was superseded by BPAP, which is more potent, selective, and also enhances serotonin.[8][1][2][3][9][10] There has been interest in PPAP for potential clinical use in humans,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]
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Pharmacology
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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]
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Chemistry
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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][14][1][2][5][16]
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 (IC50 = 1,013 nM and 2,596 nM, respectively) and are inactive as dopamine releasing agents in vitro.[17] Another similar analogue of PPAP is N,α-diethylphenethylamine (DEPEA), which is a norepinephrine–dopamine releasing agent and/or reuptake inhibitor.[18][19][12] 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.[10][20] 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.[20][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 acronym)[21] or with the cephamycin antibiotic cefoxitin (MK-306—same developmental code name).[22][23][24]
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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.[25][26][27][28][29][30][7][4][31] 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.[32][33][34]
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]
See also
References
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