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| Other names | (–)-1-(Benzofuran-2-yl)-2-propylaminopentane; (–)-BPAP;R-(–)-BPAP; BFPAPn; BFPAP; (αR)-N,α-Dipropyl-2-benzofuranethanamine;[1] FPFS-1169[2] |
| Routes of administration | By mouth[3] |
| Drug class | Monoaminergic activity enhancer |
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| Formula | C16H23NO |
| Molar mass | 245.366 g·mol−1 |
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(–)-Benzofuranylpropylaminopentane (BPAP; developmental code nameFPFS-1169) is anexperimental drug related toselegiline which acts as amonoaminergic activity enhancer (MAE).[4][5][6][2] It isorally active in animals.[3]
BPAP is a highlypotent MAE and enhances thenerve impulse propagation-mediated release ofserotonin,norepinephrine, anddopamine.[4][7][5][6] At much higher concentrations, BPAP is also amonoamine reuptake inhibitor, specifically of dopamine and norepinephrine and to a much lesser extent of serotonin.[8] BPAP producespsychostimulant-like effects in animals, with these effects mediated by its MAE actions.[7][9][10] The drug is asubstituted benzofuranderivative andtryptamine relative structurally related tophenylpropylaminopentane (PPAP).[5][7][11]
BPAP was first described in 1999.[12][11] There has been interest in BPAP for potential clinical use in humans, including in the treatment ofParkinson's disease,Alzheimer's disease, anddepression.[4][12][7] There has also been interest in BPAP to help slowaging.[4][13]
BPAP is amonoaminergic activity enhancer (MAE).[11] It stimulates theimpulse propagation mediated release of themonoamine neurotransmittersserotonin,dopamine, andnorepinephrine in the brain.[11] However, whereas the related MAEphenylpropylaminopentane (PPAP) is only acatecholaminergic activity enhancer (CAE), BPAP enhances both serotonin and thecatecholamines.[11] In addition, BPAP is a more potent MAE than PPAP.[11]
Unlikepsychostimulants likeamphetamine, which aremonoamine releasing agents that induce release of a flood of monoamine neurotransmitters in an uncontrolled manner, BPAP instead only increases the amount of neurotransmitter that is released when aneuron is stimulated by receiving an impulse from a neighbouring neuron.[3][14] As such, while both amphetamine and BPAP increase the amount of neurotransmitters that are released, amphetamine causes neurons to dump neurotransmitter stores into thesynapse regardless of external input, while with BPAP the pattern of neurotransmitter release is not changed.[3][14] Instead, when the neuron would normally release neurotransmitter, a larger amount than normal is released with BPAP.[3][14]
In anin vivo rodent study, BPAP was found to maximally increase dopamine levels in thestriatum by 44%, in thesubstantia nigra by 118%, and in theolfactory tubercle by 57%; norepinephrine levels in thelocus coeruleus by 228%; and serotonin levels in theraphe nucleus by 166%.[15][11] MAEs, including BPAP, have a peculiar and characteristicbimodalconcentration–response relationship, with twobell-shaped curves of MAE activity across tested concentration ranges.[5][7][15][16][17][18][19] Hence, there is a narrow concentration range for optimalpharmacodynamic activity.[7]
The actions of BPAP and other MAEs are distinct from those ofmonoamine reuptake inhibitors andmonoamine oxidase inhibitors.[5][12][20] Whereas BPAP enhances the nerve stimulation-induced release of serotonin, norepinephrine, and dopamine in the ratbrain stemin vitro, theselectivenorepinephrine reuptake inhibitordesipramine (desmethylimipramine), theselective serotonin reuptake inhibitorfluoxetine, the selectiveMAO-A inhibitorclorgyline, the selectiveMAO-B inhibitorlazabemide, and the potentdopamine receptor agonistsbromocriptine andpergolide were all ineffective.[5][12][20]
Recent findings have suggested that knownsynthetic MAEs like BPAP may exert their effects viatrace amine-associated receptor 1 (TAAR1)agonism.[17][16] This was evidenced by the TAAR1antagonistEPPTB reversing its MAE effects, among other findings.[17][16] Another compound,rasagiline, has likewise been found to reverse the effects of MAEs, and has been proposed as a possible TAAR1 antagonist.[16] The MAE effects of BPAP, for instance on dopamine, can be blocked bymonoamine reuptake inhibitors, likenomifensine.[17] This is thought to be because BPAP uses themonoamine transporters, like thedopamine transporter, to enter monoaminergic neurons and then mediates its MAE effects viaintracellular TAAR1 activation whilst inside ofpre-synaptic nerve terminals.[17]
Other compounds which produce MAE effects are theendogenoustrace aminesphenethylamine andtryptamine, theMAO-Binhibitorselegiline (L-deprenyl), andphenylpropylaminopentane (PPAP).[5] However, BPAP is the mostpotent MAE known, with 130 times thein vivo potency of selegiline,in vitro activity at concentrations in thefemtomolar topicomolar range, andin vivo activity at microgram doses.[4][7][5][6]
BPAPincreases locomotor activity, a measure ofpsychostimulant-like effect, in normal rats, and reverseshypolocomotion inreserpine-treated rats.[7][9][10] These effects are reversed by the dopamineD1 receptorantagonistSCH-23390 but not by the dopamineD2 receptor antagonistsulpiride, suggesting that they are mediated by the dopaminergic system.[7][9] Unlike amphetamines, but similarly to selegiline, BPAP is not expected to havemisuse potential.[4] BPAP antagonizestetrabenazine-induced inhibition of learning in the shuttle box.[7] It has been found to haveneuroprotective effects similar to those of selegiline in someanimal models.[12] Following a peak in adolescence, monoamine release in the brain declines with age in rodents and this is associated with reduced behavioral activity.[15][6][21] Rodent studies have found that MAEs like BPAP and selegiline augment brain monoamine release, slow age-related monoaminergicneurodegeneration, help to preserve behavioral activity with age, and prolong lifespan.[15][6][22][21][13]
In addition to its MAE actions, BPAP is amonoamine reuptake inhibitor at higher concentrations.[8] ItsIC50Tooltip half-maximal inhibitory concentration values in terms ofbinding affinity for thedopamine transporter,norepinephrine transporter, andserotonin transporter are 16 ± 2 nM, 211 ± 61 nM, and 638 ± 63 nM, respectively.[8] Conversely, itsIC50 values for inhibition of dopamine, norepinephrine, and serotonin reuptake are 42 ± 9 nM, 52 ± 19 nM, and 640 ± 120 nM, respectively.[8] It has no classicalmonoamine releasing agent actions, in contrast toamphetamines.[5][11] It has been said that the monoamine reuptake inhibition of BPAP is not of pharmacological significance at the much lower concentrations that have MAE activity.[4]
While selegiline is a potentmonoamine oxidase inhibitor (MAOI), BPAP is only a weakMAO-A inhibitor at high concentrations, and at low concentrations produces only MAE effects.[5][11] It is 10,000-fold less potent than the potent MAO-A inhibitorclorgyline in terms of MAO-A inhibition.[11] The weak MAO-A inhibition of BPAP is said to be without pharmacological significance.[4][11] BPAP has relatively weak affinity for theα2-adrenergic receptor.[4][11] However, this occurs at concentrations well below its MAE actions.[11] The drug is also a weak agonist of thesigma receptor likewise at high concentrations.[7][19][23][24]
Thepharmacokinetics of BPAP have been studied in rodents.[3] It iswell-absorbed withparenteral andoralroutes and shows substantial oralbioavailability.[3]Peak levels are reached within 30 to 60 minutes.[3] There is a second peak after 4 hours due toenterohepatic circulation.[3] It crosses theblood–brain barrier anddistributes into variousbrain areas.[3] The drug is notmetabolized bymonoamine oxidase.[5] BPAP is preferentiallyeliminated inurine and to a lesser extent infeces.[3] Itselimination half-life was 5.5 to 5.8 hours.[3] The drug is recovered more than 90% in urine and feces 72 hours after administration.[3]
BPAP (1-(benzofuran-2-yl)-2-propylaminopentane) is asubstituted benzofuranderivative andtryptamine relative and was derived fromstructural modification ofphenylpropylaminopentane (PPAP).[5][7][11] It was developed by replacement of thebenzenering in PPAP with abenzofuran ring.[11][25]
The compound is generally studied and used as theR(–)-enantiomer,R(–)-BPAP or simply (–)-BPAP (FPFS-1169).[5][4][11][26][2] This enantiomer is morepotent than theS(+)-enantiomer (FPFS-1170).[17][14][2]
Indolylpropylaminopentane (IPAP), ananalogue of BPAP, is a MAE for serotonin, norepinephrine, and dopamine that was derived from tryptamine.[15][17][25] Unlike BPAP, it shows some selectivity for serotonin, with its maximal impact on this neurotransmitter occurring at 10-fold lower concentrations than for norepinephrine or dopamine.[17][25]
A derivative of BPAP,3-F-BPAP, has weak MAE activity and has been found toantagonize the MAE actions of BPAP.[7][27] These findings suggest that 3-F-BPAP interacts with the samereceptor orbiological target as BPAP and acts as a MAE antagonist.[7][27]
Enantioselectivesynthesis of (–)-BPAP has been described.[14]
BPAP was first described in thescientific literature in 1999.[12][6][11] It wasderived viastructural modification ofphenylpropylaminopentane (PPAP).[4][11][25] It was discovered by the developers ofselegiline, includingJózsef Knoll and colleagues like Ildikó Miklya.[6][11] PPAP had previously been derived by modification of selegiline.[6][28]
BPAP has been studied inpreclinical research for potential treatment ofAlzheimer's disease,Parkinson's disease,depression, andaging.[4][12][7][13] It has been found to be active in multipleanimal models ofantidepressant action.[29] It also attenuates reinstatement ofmethamphetamine-seeking behavior in rodents.[30] The drug has been proposed for potentialclinical development for use in humans.[4][3] An effective dosage of BPAP of 0.1 mg/day, one-tenth of that of the less-potent compound selegiline (1 mg/day), has been suggested for study and use in humans.[4][7]
Among catecholaminergic-serotonergic enhancers, (–)-1-phenyl-2-propylaminopentane [(–)-PPAP] and R-(–)-(benzofuran-2-yl)-2-propylaminopentane [R-(–)-BPAP, the development number; FPFS-1169] are the most promising agents (Knoll et al., 1999). [...] Fig. 1. Chemical structure and abbreviations of used BPAP derivatives. FPFS-1169 and FPFS-1170: R-(–)- and S-(+)-1-(benzofuran-2-yl)-2-propylamino-pentane hydrochloride, [...]
It is obvious that the bell-shape dose-response curve in the nanomolecular range is responsible for the highly specific enhancer effect of the compound. In contrast, the dose-response curve in the macromolecular range has probably nothing to do with the enhancer regulation and is therefore of lower physiological significance. Recent studies revealed that in this macromolecular dose range (–)-BPAP binds to sigma receptors [2,11].
