1-Phenyl-2-propylaminopentane (PPAP), also known as α,''N''-dipropylphenethylamine (DPPEA) and by the developmental code name MK-306, is an

experimental drug An experimental drug is a medicinal product (a drug or vaccine) that has not yet received drug approval, approval from governmental regulatory agency, regulatory authorities for routine use in human medicine, human or veterinary medicine. A medicin ...

related to

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

which acts as a

catecholaminergic activity enhancer Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of drugs that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs ar ...

(CAE). PPAP is a CAE and enhances the

nerve impulse An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

propagation-mediated release of

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

and

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. It produces

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

-like effects in animals. The drug is a

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

and

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

and was derived from selegiline. PPAP was first described in the literature in 1988 and in the first major paper in 1992. It led to the development of the improved

monoaminergic activity enhancer Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of drugs that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs ar ...

(MAE)

benzofuranylpropylaminopentane (–)-Benzofuranylpropylaminopentane (BPAP; developmental code name FPFS-1169) is an experimental drug related to selegiline which acts as a monoaminergic activity enhancer (MAE). It is orally active in animals. BPAP is a highly potent MAE ...

(BPAP) in 1999. PPAP was a reference compound for studying the MAE system for many years. However, it was superseded by BPAP, which is more potent, selective, and also enhances

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

. There has been interest in PPAP for potential clinical use in humans, including in the treatment of depression,

attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD), and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

Pharmacology

Pharmacodynamics

Catecholaminergic activity enhancer

PPAP is classified as a

(CAE), a drug that stimulates the

impulse Impulse or Impulsive may refer to: Science * Impulse (physics), in mechanics, the change of momentum of an object; the integral of a force with respect to time * Impulse noise (disambiguation) * Specific impulse, the change in momentum per unit ...

propagation-mediated

release Release may refer to: * Art release, the public distribution of an artistic production, such as a film, album, or song * Legal release, a legal instrument * News release, a communication directed at the news media * Release (ISUP), a code to i ...

of the catecholamine neurotransmitters

and

in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

. Unlike stimulants such as

, 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 A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

is stimulated by receiving an impulse from a neighboring neuron. Both amphetamine and (–)-PPAP promote the release of monoamines; however, while amphetamine causes neurons to release neurotransmitter stores into the

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

regardless of external input, (–)-PPAP does not influence the pattern of neurotransmitter release and instead releases a larger amount of neurotransmitters than normal. Recent findings have suggested that known

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

s (MAEs) like PPAP, BPAP, and

may exert their effects via

trace amine-associated receptor 1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

(TAAR1)

agonism Agonism (from Greek 'struggle') is a political and social theory that emphasizes the potentially positive aspects of certain forms of conflict. It accepts a permanent place for such conflict in the political sphere, but seeks to show how indivi ...

. This was evidenced by the TAAR1

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.EPPTB reversing the MAE effects of BPAP and selegiline, among other findings. Another compound,

rasagiline Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advan ...

, has likewise been found to reverse the effects of MAEs, and has been proposed as a possible TAAR1 antagonist. The

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

for PPAP in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s is greater than that of amphetamine while producing comparable improvements in

learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, Attitude (psychology), attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and ...

, retention, and

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

effects. It has been found to reduce deficits induced by the

dopamine depleting agent Monoamine-depleting agents are a group of drugs which reversibly deplete one or more of the monoamine neurotransmittersserotonin, dopamine, and norepinephrine. One mechanism by which these agents act is by inhibiting reuptake by the vesicular m ...

tetrabenazine Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the US Food and Drug Administration (FDA) approved the use of tet ...

in the shuttle box learning test in rats. PPAP and selegiline are much less potent than BPAP as MAEs. Whereas PPAP and selegiline are active at doses of 1 to 5mg/kg ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' in rats, BPAP is active at doses of 0.05 to 10mg/kg. BPAP is 130times as potent as selegiline in the shuttle box test. In contrast to BPAP however, the MAE effects of PPAP and selegiline are not reversed by the BPAP

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.3-F-BPAP 3-F-BPAP is a trifluorinated derivative of benzofuranylpropylaminopentane (BPAP) and is an antagonist of the monoaminergic activity enhancer (MAE) effects of the tryptamine-related BPAP. Conversely, 3-F-BPAP does not antagonize the catecholamin ...

. 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

Other actions

Unlike the related CAE

, (–)-PPAP has no activity as a

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

Chemistry

PPAP, also known as α,''N''-dipropylphenethylamine (DPPEA) or as α-desmethyl-α,''N''-dipropylamphetamine, is a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

and

. It was derived from structural modification of

(L-deprenyl; (''R'')-(–)-''N'',α-dimethyl-''N''-2-propynylphenethylamine). Both

racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

PPAP and subsequently its more active (–)- or (2''R'')-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

(–)-PPAP have been employed in the literature. PPAP is similar in

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

to propylamphetamine (''N''-propylamphetamine; NPA; PAL-424), but has an α-

propyl In organic chemistry, a propyl group is a three-carbon alkyl substituent with chemical formula for the linear form. This substituent form is obtained by removing one hydrogen atom attached to the terminal carbon of propane. A propyl substituent ...

chain A chain is a serial assembly of connected pieces, called links, typically made of metal, with an overall character similar to that of a rope in that it is flexible and curved in compression but linear, rigid, and load-bearing in tension. A ...

instead of an α-

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

. 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 Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

s ( = 1,013nM and 2,596nM, respectively) and are inactive as

dopamine releasing agent A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the Body (biology), body and/or brain. No binding selectivity, selective DRAs are currently known. However, non-selective DRAs, including norepinephrin ...

s ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

''. Another similar analogue of PPAP is ''N'',α-diethylphenethylamine (DEPEA), which is a

norepinephrine–dopamine releasing agent A norepinephrine–dopamine releasing agent (NDRA) is a type of drug which induces the synapse, release of norepinephrine (and epinephrine) and dopamine in the body and/or brain. Many of these are amphetamine type stimulants. Examples Examples ...

and/or

reuptake inhibitor Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracel ...

. A more well-known derivative of APPEA related to PPAP is the

cathinone Cathinone (; also known as β-ketoamphetamine) is a monoamine alkaloid found in the shrub ''Catha edulis'' (khat) and is chemically similar to ephedrine, cathine, methcathinone and other amphetamines. It is probably the main contributor to t ...

pentedrone (α-propyl-β-keto-''N''-methylphenethylamine), which is a norepinephrine–dopamine reuptake inhibitor. A related MAE, BPAP, is a

substituted benzofuran The substituted benzofurans are a class of chemical compounds based on the heterocyclic compound, heterocyclic and polycyclic compound, polycyclic compound benzofuran. Many medicines use the benzofuran core as a scaffold, but most commonly the t ...

derivative and

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

relative that was derived from structural modification of PPAP. It was developed by replacement of the

benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...

ring (The) Ring(s) may refer to: * Ring (jewellery), a round band, usually made of metal, worn as ornamental jewelry * To make a sound with a bell, and the sound made by a bell Arts, entertainment, and media Film and TV * ''The Ring'' (franchise), a ...

in PPAP with a

benzofuran Benzofuran is the heterocyclic compound consisting of fused benzene and furan rings. This colourless liquid is a component of coal tar. Benzofuran is the structural nucleus (parent compound) of many related compounds with more complex stru ...

ring. 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 Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...

ring. PPAP (MK-306) and its (–)-enantiomer (–)-PPAP must not be confused with the

sigma receptor Sigma receptors (σ-receptors) are protein receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 rec ...

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

''R''(−)-''N''-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane ((–)-PPAP—same acronym) or with the

cephamycin Cephamycins are a group of β-lactam antibiotics. They are very similar to cephalosporins, and the cephamycins are sometimes classified as cephalosporins. Like cephalosporins, cephamycins are based upon the cephem nucleus. Unlike most cephalospor ...

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

cefoxitin (MK-306—same developmental code name).

History

Racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

PPAP (MK-306) was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

in 1988 and a series of papers characterizing it were published in the early 1990s. The first major paper on the drug was published in 1992. It was synthesized by József Knoll and colleagues. The potencies of the different

s of PPAP were assessed in 1994. Subsequent papers have employed (–)-PPAP. Several

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

s of PPAP have been published. The development of PPAP was critical in elucidating that the CAE effects of

are unrelated to its

monoamine oxidase inhibition Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especia ...

. For many years, PPAP served as a reference compound in studying MAEs. However, it was eventually superseded by BPAP, which was discovered in 1999. This MAE is potent and selective than PPAP and, in contrast to PPAP and selegiline, also enhances

Research

PPAP has been proposed as a potential therapeutic agent for

(ADHD),

, and depression based on preclinical findings. The developers of PPAP attempted to have it clinically studied, but were unsuccessful and it was never assessed in humans.

References

{{Phenethylamines Alpha-Propylphenethylamines Antidepressants Antiparkinsonian agents Designer drugs Drugs with unknown mechanisms of action Enantiopure drugs Experimental drugs Monoaminergic activity enhancers Pro-motivational agents Stimulants TAAR1 agonists