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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 |
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Formula | C14H23N |
Molar mass | 205.345 g·mol−1 |
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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in 1999.[1][3] PPAP was a reference compound for studying the MAE system for many years.[1][2][3] However, it was superseded by BPAP, which is more potent, selective, and also enhances serotonin.[8][1][2][3][9][10] There has been interest in PPAP for potential clinical use in humans,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]
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.
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.
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).
KnollMiklyaKnoll1996
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