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). <ref name="GasznerMiklya2006"> PPAP is a CAE and enhances the nerve impulse propagation-mediated release of norepinephrine and dopamine. It produces psychostimulant-like effects in animals. The drug is a phenethylamine and amphetamine derivative 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 (MAE) benzofuranylpropylaminopentane (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 However, it was superseded by BPAP, which is more potent, selective, and also enhances serotonin. 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.

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. 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. 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. 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. This was evidenced by the TAAR1 antagonist EPPTB reversing the MAE effects of BPAP and selegiline, among other findings. Another compound, rasagiline, has likewise been found to reverse the effects of MAEs, and has been proposed as a possible TAAR1 antagonist. The therapeutic index for PPAP in animal models is greater than that of amphetamine while producing comparable improvements in learning, retention, and antidepressant effects. It has been found to reduce deficits induced by the dopamine depleting agent tetrabenazine 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 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 3-F-BPAP. 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.

Other actions

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

Chemistry

PPAP, also known as α,N-dipropylphenethylamine or as α-desmethyl-α,N-dipropylamphetamine, is a substituted phenethylamine and amphetamine derivative. It was derived from structural modification of selegiline ( L -deprenyl; (R)-(–)-N,α-dimethyl-N-2-propynylphenethylamine). Both racemic PPAP and subsequently its more active (–)- or (2R)-enantiomer (–)-PPAP have been employed in the literature. 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 (IC50 = 1,013nM and 2,596nM, respectively) and are inactive as dopamine releasing agents in vitro. A related MAE, BPAP, is a substituted benzofuran derivative and tryptamine relative that was derived from structural modification of PPAP. It was developed by replacement of the benzene ring in PPAP with a benzofuran 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 ring. 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) or with the cephamycin antibiotic cefoxitin (MK-306—same developmental code name).

History

Racemic PPAP (MK-306) was first described in the scientific literature 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 enantiomers of PPAP were assessed in 1994. Subsequent papers have employed (–)-PPAP. Several patents of PPAP have been published. The development of PPAP was critical in elucidating that the CAE effects of selegiline are unrelated to its monoamine oxidase inhibition. 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 serotonin.

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