Indolylpropylaminopentane Explained

Indolylpropylaminopentane (IPAP) is a monoaminergic activity enhancer (MAE) that is closely related to benzofuranylpropylaminopentane (BPAP) and phenylpropylaminopentane (PPAP).^{[1] [2] [3] [4] [5]} It is a tryptamine derivative and the corresponding analogue of PPAP and BPAP with an indole ring instead of a benzene ring or benzofuran ring, respectively. MAEs are agents that enhance the action potential-mediated release of monoamine neurotransmitters.

IPAP is a MAE of serotonin, norepinephrine, and dopamine. However, IPAP acts preferentially as a MAE of serotonin and is about 10-fold more potent in enhancing serotonin than in enhancing norepinephrine or dopamine. This is in contrast to BPAP, which is of similar potency as a MAE of serotonin and the catecholamines. It is also in contrast to PPAP and selegiline, which act exclusively as catecholaminergic activity enhancers (CAEs) and do not enhance serotonin.^{[6] [7] [8]} Hence, IPAP is a representative selective serotonergic activity enhancer (SAE) at lower doses.

IPAP is more potent as a MAE than PPAP and selegiline but is less potent than BPAP. As with BPAP and PPAP, the negative enantiomer (i.e., R(–)-IPAP) is more biologically active as a MAE and is often the employed compound. The effects of MAEs appear to be mediated by intracellular TAAR1 agonism coupled with uptake by monoamine transporters into monoaminergic neurons.

In contrast to amphetamines, IPAP has no classical monoamine releasing agent actions. It is a weak MAO-A inhibitor similarly to BPAP.

IPAP was first described in the scientific literature in 2001, following BPAP in 1999.^[9]

Notes and References

1. Book: Knoll J . The Brain and Its Self: A Neurochemical Concept of the Innate and Acquired Drives . Enhancer Regulation: A Neurochemical Approach to the Innate and Acquired Drives . Springer-Verlag . Berlin/Heidelberg . 2005 . 978-3-540-23969-7 . 10.1007/3-540-27434-0_4 . 25–94 . Fig. 3.10. The chemical structure and pharmacological spectrum of tryptamine and two of its most representative synthetic derivatives. Taken from Knoll (2001). [Fig. 3.10.: IPAP has the enhancer effect, has no releasing effect, and is a weak MAO-A inhibitor similarly to BPAP.].
2. Yoneda F, Moto T, Sakae M, Ohde H, Knoll B, Miklya I, Knoll J . 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 . May 2001 . 11377178 . 10.1016/s0968-0896(01)00002-5 . Group 4. Indolyl, benzothienyl and benzofuryl derivatives of PPAP (Table 4). The indol-3-yl analogue of PPAP (IPAP, 7a) and its (—) and (+)enantiomers ((—)IPAP and (+)IPAP) (see Table 5) were used as reference substances for the indol analogues of PPAP. (—)IPAP was about 5 times more potent than PPAP in the shuttle box experiment. [...] IPAP was less potent than PPAP. [...] (-)BPAP, the most potent member of the group, was about 100 times more potent than PPAP in the shuttle box experiment. [...] The two most effective substances, (—)IPAP and (—)BPAP enhanced the release of dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe in 0.5 and 0.1 gg kg (1.78 and 0.36 nmol kg), respectively (Table 7). The release of dopamine from the substantia nigra of rats treated for 3 weeks with (—)IPAP or (—)BPAP demonstrates that the compounds enhanced significantly the release of dopamine in rats treated with low or high doses, while the release of noradrenaline from the locus coeruleus and serotonin from the raphe was significantly increased only in rats treated with a low dose of (—)IPAP or (—)BPAP. In the case of serotonin, high dose treatment even inhibited the release of the transmitter. [...] (—)PPAP was about twice as potent as (—)deprenyl in [antagonism of tetrabenazine in the shuttle box test]. Of the newly synthesized compounds, NPAP was as active as PPAP, the further order of potency was as follows: IPAP < MPAP < BPAP. [...] (—)BPAP, was [...] about 130 times more potent than (—)deprenyl. [...] [Plus tables].
3. Harsing LG, Knoll J, Miklya I . Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum . Int J Mol Sci . 23 . 15 . August 2022 . 8543 . 35955676 . 9369307 . 10.3390/ijms23158543 . free . Figure 1. The chemical structure [...] and enhancer substances (PPAP, IPAP, BPAP). [...] The most well-characterized member of the enhancers is (—)BPAP [...] besides PPAP and IPAP (Figure 1). In the case of PPAP, IPAP, and BPAP, the negative enantiomers (R configurations) proved to be biologically more active [29]. [...] Although compounds shown in Figure 1 can be derived from phenylethylamine or other trace amines, there are differences in the ring or the attached alkylamine side chains. A phenyl ring can be found in the structure of (—)PPAP and (±)methamphetamine, whereas there are indole or benzofuran ring in (—)IPAP or (—)BPAP, respectively. [...] (—)IPAP exerts its major effect on serotonergic transmission, whereas (—)BPAP shows approximatively equal potency on both biogenic amine transmissions [26]. [...] Compounds ((—)PPAP, (—)IPAP, (—)BPAP) (Figure 1) that contain 2-propyl- aminopentane moiety are selective enhancers of the impulse propagation mediated-release of catecholamines or serotonin, but leave MAO activity practically unchanged [25]. [...] The enhancer compounds (—)PPAP, (—)IPAP; and (—)BPAP were without effect on non-vesicular [3H]dopamine release. [...] Figure 3B demonstrates that the enhancer compounds (—)PPAP, (—)IPAP, and (—)BPAP, which all contain propyl group substitutions on the nitrogen and carbon atoms but with various rings attached (phenyl, indole, and benzofuran) to the side chain, do not possess releasing ability [...].
4. Harsing LG, Timar J, Miklya I . Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline . Int J Mol Sci . 24 . 17 . August 2023 . 13334 . 37686140 . 10487936 . 10.3390/ijms241713334 . free . Compounds exhibiting these unique pharmacological actions are designated as catecholaminergic activity enhancer (CAE) drugs, and the most widely investigated compounds of this series are (−)PPAP ((−)-1-phenyl-2-propylaminopentane, Figure 1), and its indole (−)IPAP ((−)-1-(indol-3-yl)-2-propylaminopentane), and benzofuran ((−)BPAP ((R)-(−)-1-(benzofuran-2-yl)-2-propylaminopentane) analogs [14]. [...] Previous investigations of other members of the N,α,-dipropylarylethylamine series ((−)PPAP, (−)IPAP) indicated that the catecholamine activity enhancer effect is not related to MAO inhibition [13,14]..
5. Web site: Knoll J . Discovery of the Enhancer Regulation in the Mammalian Brain and the Development of Synthetic Enhancer Substances: A Chance to Significantly Improve the Quality and Prolong the Duration of Human Life . International Network for the History of Neuropsychopharmacology (INHN) . 2016 . Fig.19 shows the chemical structure and pharmacological spectrum of tryptamine; (-)-IPAP, the simplest tryptamine-derived, synthetic enhancer substance; and (-)-BPAP, the tryptamine-derived most representative enhancer substance. [Fig.19.: IPAP has the enhancer effect, has no releasing effect, and is a weak MAO-A inhibitor similarly to BPAP.].
6. Shimazu S, Miklya I . Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 28 . 3 . 421–427 . May 2004 . 15093948 . 10.1016/j.pnpbp.2003.11.016 . 37564231 .
7. Miklya I . The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015) . Molecular Psychiatry . 21 . 11 . 1499–1503 . November 2016 . 27480491 . 10.1038/mp.2016.127 . 205202709 . free .
8. Knoll J . Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives . Neurochemical Research . 28 . 8 . 1275–1297 . August 2003 . 12834268 . 10.1023/a:1024224311289 .
9. Gaszner P, Miklya I . 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 . January 2006 . 16023777 . 10.1016/j.pnpbp.2005.06.004 . 26570703 .