monoaminergic activity enhancer

A few endogenous MAEs have been identified, including the trace amines β-phenylethylamine (PEA), tyramine, and tryptamine.{{cite journal | vauthors = Knoll J, Miklya I, Knoll B, Markó R, Rácz D | title = Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain | journal = Life Sci | volume = 58 | issue = 23 | pages = 2101–2114 | date = 1996 | pmid = 8649195 | doi = 10.1016/0024-3205(96)00204-4 | url = }} At a concentration of 16{{nbsp}}μM (1.6 × 10⁻⁵ M), β-phenylethylamine has been shown to act as a MAE for norepinephrine (2.6-fold increase), dopamine (1.3-fold increase), and serotonin (2.3-fold increase) in the rat brainstem in vitro. Conversely, tryptamine has been found to act as a MAE for serotonin (3.6-fold increase) at a concentration of 1.3{{nbsp}}μM (1.3 × 10⁻⁶ M) and as a MAE for norepinephrine (1.9-fold increase) and dopamine (1.3-fold increase) at a concentration of 13{{nbsp}}μΜ (1.3 × 10⁻⁵ M) in the rat brainstem in vitro. It is apparent that tryptamine at a concentration of 1.3{{nbsp}}μΜ is a much more effective MAE of serotonin than is β-phenylethylamine at a concentration of 16{{nbsp}}μM. Hence, tryptamine is a substantially more potent MAE of serotonin than β-phenylethylamine, whereas β-phenylethylamine is a slightly more potent MAE of norepinephrine than tryptamine. It has been suggested that these selectivities may indicate the existence of multiple MAE receptors for these compounds. Tyramine has been shown to act as a MAE of norepinephrine, dopamine, and serotonin in the rat brainstem in vitro similarly to β-phenylethylamine. β-Phenylethylamine and tyramine additionally act as potent monoamine releasing agents of norepinephrine and dopamine at higher concentrations.{{Cite journal |last=Miklya |first=I. |date=November 2016 |title=The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015) |journal=Molecular Psychiatry |volume=21 |issue=11 |pages=1499–1503 |doi=10.1038/mp.2016.127 |issn=1476-5578 |pmid=27480491|s2cid=205202709 |doi-access=free }} The MAE and monoamine releasing agent actions of these compounds are mechanistically distinct and they have been referred to as "mixed-acting" monoaminergic potentiators.

The synthetic MAE benzofuranylpropylaminopentane (BPAP) has been found to be far more potent as a MAE and to exert MAE and related effects at much lower concentrations than known endogenous MAEs like β-phenylethylamine and tryptamine. For example, BPAP has been found to have peak effects at a concentration of 10⁻¹⁴{{nbsp}}M (femtomolar to picomolar range). It has been hypothesized that the very high potency of BPAP may foreshadow the existence of much more potent endogenous MAEs than currently known compounds like β-phenylethylamine and tryptamine that have yet to be identified and may be the true key endogenous mediators for this system.

β-Phenylethylamine, tryptamine, and tyramine when administered to animals are ineffective as MAEs in vivo due to very rapid breakdown by monoamine oxidase (MAO). However, monoamine oxidase inhibitors (MAOIs), specifically MAO-B inhibitors like selegiline, can dramatically potentiate β-phenylethylamine by inhibiting its metabolism and thereby allow for it to produce significant pharmacodynamic effects.{{cite book | vauthors = Yasar S, Goldberg JP, Goldberg SR | chapter = Are metabolites of l-deprenyl (Selegiline) useful or harmful? Indications from preclinical research | title = Deprenyl — Past and Future | series = Journal of Neural Transmission. Supplementum | pages = 61–73 | date = January 1, 1996 | volume = 48 | pmid = 8988462 | doi = 10.1007/978-3-7091-7494-4_6 | isbn = 978-3-211-82891-5 }}{{cite journal | vauthors = Timár J, Knoll B | title = The effect of repeated administration of (-) deprenyl on the phenylethylamine-induced stereotypy in rats | journal = Arch Int Pharmacodyn Ther | volume = 279 | issue = 1 | pages = 50–60 | date = January 1986 | pmid = 3083795 | doi = | url = }}{{cite journal | vauthors = Timár J, Gyarmati Z, Tekes K, Härsing GL, Knoll J | title = Further proof that (-)deprenyl fails to facilitate mesolimbic dopaminergic activity | journal = Pharmacol Biochem Behav | volume = 46 | issue = 3 | pages = 709–714 | date = November 1993 | pmid = 8278449 | doi = 10.1016/0091-3057(93)90566-c | url = }}{{cite journal | vauthors = McKean AJ, Leung JG, Dare FY, Sola CL, Schak KM | title = The Perils of Illegitimate Online Pharmacies: Substance-Induced Panic Attacks and Mood Instability Associated With Selegiline and Phenylethylamine | journal = Psychosomatics | volume = 56 | issue = 5 | pages = 583–587 | date = 2015 | pmid = 26198572 | doi = 10.1016/j.psym.2015.05.003 | url = }} Tyramine, unlike β-phenylethylamine and tryptamine, is unable to cross the blood–brain barrier, which additionally limits its capacity for centrally mediated effects.{{cite journal | vauthors = Gillman PK | title = A reassessment of the safety profile of monoamine oxidase inhibitors: elucidating tired old tyramine myths | journal = J Neural Transm (Vienna) | volume = 125 | issue = 11 | pages = 1707–1717 | date = November 2018 | pmid = 30255284 | doi = 10.1007/s00702-018-1932-y | url = }}

Selegiline (L-deprenyl) (a phenylethylamine derivative) is used as an antiparkinsonian agent and antidepressant and exhibits CAE effects independent of its monoamine oxidase inhibition. It has been shown to enhance both impulse-evoked norepinephrine and dopamine release. Selegiline shows a bimodal concentration–response relationship in terms of its CAE actions for dopamine activity in the striatum. Besides enhancing catecholaminergic activity, it has additionally been found to decrease serotonergic activity. Selegiline's metabolite desmethylselegiline has also been found to be active as a CAE.{{cite journal | vauthors = Miklya I | title = (-)-deprenil, az N-metilprogargilamin-1-aminoindan (J-508) és a J-508 dezmetil analógjának (rasagilin) összehasonlító farmakológiai analízise | trans-title = A comparison of the pharmacology of (-)-deprenyl to N-methylpropargylamine-1-aminoindane (J-508) and rasagiline, the desmethyl-analogue of J-508 | language = Hungarian | journal = Neuropsychopharmacol Hung | volume = 10 | issue = 1 | pages = 15–22 | date = March 2008 | pmid = 18771016 | doi = | url = https://mppt.hu/magazin/pdf/x-evfevfolyam-1-szam/a---deprenil-az-n.pdf}} Aside from selegiline and its metabolites, D-deprenyl is a CAE, with slightly lower potency than selegiline.{{cite journal | vauthors = Knoll J, Miklya I | title = Multiple, small dose administration of (-)deprenyl enhances catecholaminergic activity and diminishes serotoninergic activity in the brain and these effects are unrelated to MAO-B inhibition | journal = Arch Int Pharmacodyn Ther | volume = 328 | issue = 1 | pages = 1–15 | date = 1994 | pmid = 7893186 | doi = | url = }} By extension to selegiline and D-deprenyl, the racemic form, deprenyl, is a CAE. A halogenated analogue of deprenyl, 4-fluorodeprenyl, has been found to act as a CAE as well.

The psychostimulants amphetamine (both levoamphetamine and dextroamphetamine) and methamphetamine (both levomethamphetamine and dextromethamphetamine) are CAEs like selegiline, but these drugs are also potent monoamine releasing agents and these actions overshadow the former activities.{{cite journal | vauthors = Knoll J | title = Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain | journal = CNS Drug Rev | volume = 7 | issue = 3 | pages = 317–45 | date = 2001 | pmid = 11607046 | pmc = 6494119 | doi = 10.1111/j.1527-3458.2001.tb00202.x | url = }}{{cite journal | vauthors = Knoll J | title = (-)Deprenyl (selegiline), a catecholaminergic activity enhancer (CAE) substance acting in the brain | journal = Pharmacol Toxicol | volume = 82 | issue = 2 | pages = 57–66 | date = February 1998 | pmid = 9498233 | doi = 10.1111/j.1600-0773.1998.tb01399.x | url = }} Levomethamphetamine, levoamphetamine, and dextroamphetamine are all similarly potent as CAEs and compared to selegiline, but are substantially more potent as CAEs than dextromethamphetamine. Besides acting as CAEs, levomethamphetamine and dextromethamphetamine diminish serotonergic activity, similarly to selegiline, whereas levoamphetamine and dextroamphetamine do not do so.

Phenylpropylaminopentane (PPAP) is a CAE for norepinephrine and dopamine that was derived from selegiline and is a phenethylamine derivative.{{Cite journal |last1=Knoll |first1=J. |last2=Knoll |first2=B. |last3=Török |first3=Z. |last4=Timár |first4=J. |last5=Yasar |first5=S. |date=1992 |title=The pharmacology of 1-phenyl-2-propylamino-pentane (PPAP), a deprenyl-derived new spectrum psychostimulant |url=https://pubmed.ncbi.nlm.nih.gov/1356324/ |journal=Archives Internationales de Pharmacodynamie et de Therapie |volume=316 |pages=5–29 |issn=0003-9780 |pmid=1356324}} In contrast to selegiline, it lacks monoamine oxidase inhibition and hence is much more selective in its actions.{{cite journal | vauthors = Csaba G, Kovács P, Pállinger E | title = Acute and delayed effect of (-) deprenyl and (-) 1-phenyl-2-propylaminopentane (PPAP) on the serotonin content of peritoneal cells (white blood cells and mast cells) | journal = Cell Biochemistry and Function | volume = 24 | issue = 1 | pages = 49–53 | date = January–February 2006 | pmid = 15584092 | doi = 10.1002/cbf.1183 | s2cid = 11027835 }} Indolylpropylaminopentane (IPAP) is a MAE for serotonin, norepinephrine, and dopamine that was derived from PPAP and is a tryptamine derivative. It shows some selectivity for serotonin, with its maximal impact on this neurotransmitter occurring at 10-fold lower concentrations than for norepinephrine or dopamine. Benzofuranylpropylaminopentane (BPAP) is a MAE for serotonin, norepinephrine, and dopamine that was derived from PPAP and is related to tryptamine.{{Cite journal |last1=Magyar |first1=Kálmán |last2=Lengyel |first2=Joseph |last3=Bolehovszky |first3=Andrea |last4=Knoll |first4=Bertha |last5=Miklya |first5=Iidikó |last6=Knoll |first6=Joseph |date=2002-09-01 |title=The fate of (−)1-(benzofuran-2-yl)-2-propylaminopentane · HCl, (−)-BPAP, in rats, a potent enhancer of the impulse-evoked release of catecholamines and serotonin in the brain |url=https://doi.org/10.1007/BF03190451 |journal=European Journal of Drug Metabolism and Pharmacokinetics |language=en |volume=27 |issue=3 |pages=157–161 |doi=10.1007/BF03190451 |pmid=12365195 |s2cid=30618267 |issn=2107-0180|url-access=subscription }} It is about 130{{nbsp}}times more potent in its MAE actions than selegiline. Similarly to selegiline, BPAP shows a bimodal concentration–response relationship in its MAE effects.

In contrast to selegiline, rasagiline and its metabolite (R)-1-aminoindan do not have MAE actions.{{cite journal | vauthors = Miklya I | title = Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline | journal = Pharmacol Rep | volume = 66 | issue = 3 | pages = 453–458 | date = June 2014 | pmid = 24905523 | doi = 10.1016/j.pharep.2013.11.003 | url = }} Similarly, SU-11739 (AGN-1133; J-508), the N-methylated analogue of rasagiline and a closer analogue of selegiline, does not have MAE actions.

The mechanism of action of MAEs, for instance the trace amines, may be explained by their shared affinities for the trace amine-associated receptor 1 (TAAR1).{{cite journal | vauthors = Berry MD | title = The potential of trace amines and their receptors for treating neurological and psychiatric diseases | journal = Rev Recent Clin Trials | volume = 2 | issue = 1 | pages = 3–19 | date = January 2007 | pmid = 18473983 | doi = 10.2174/157488707779318107 | url = | quote = In addition, the compounds previously described by Knoll and colleagues [33, 34], along with a series of trace amine derivatives synthesized by Ling et al. [35] are potential TAAR ligands. Although neither of these classes of compound appear to have been examined for efficacy at TAAR, their strong structural similarity to trace amines suggests that such studies are warranted.}} Trace amines like β-phenylethylamine and tyramine bind to the TAAR1 with high affinity, whereas the affinities of other monoamines like octopamine, dopamine, and serotonin for this receptor are much lower.{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = J Neurochem | volume = 116 | issue = 2 | pages = 164–176 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x | url = }}{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA}} In addition, recent findings have suggested that known synthetic MAEs like BPAP and selegiline may exert their effects via TAAR1 activation.{{cite journal | vauthors = Harsing LG, Knoll J, Miklya I | title = Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum | journal = Int J Mol Sci | volume = 23 | issue = 15 | date = August 2022 | page = 8543 | pmid = 35955676 | pmc = 9369307 | doi = 10.3390/ijms23158543 | doi-access = free | url = }}{{cite journal | vauthors = Harsing LG, Timar J, Miklya I | title = Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline | journal = Int J Mol Sci | volume = 24 | issue = 17 | date = August 2023 | page = 13334 | pmid = 37686140 | pmc = 10487936 | doi = 10.3390/ijms241713334 | doi-access = free | url = }}{{cite journal | vauthors = Harsing LG, Szénási G, Fehér B, Miklya I | title = Regulation by Trace Amine-Associated Receptor 1 (TAAR1) of Dopaminergic-GABAergic Interaction in the Striatum: Effects of the Enhancer Drug (-)BPAP | journal = Neurochem Res | volume = 50 | issue = 2 | pages = 94 | date = February 2025 | pmid = 39903411 | pmc = 11794408 | doi = 10.1007/s11064-025-04337-7 | url = }} This was evidenced by the TAAR1 antagonist EPPTB reversing their MAE effects, among other findings. However, in an older study of MAO-B knockout mice, no non-MAO binding of radiolabeled selegiline was detected in the brain, suggesting that this agent might not act directly via a macromolecular target in terms of its MAE effects.{{cite journal | vauthors = Magyar K, Szende B, Jenei V, Tábi T, Pálfi M, Szöko E | title = R-deprenyl: pharmacological spectrum of its activity | journal = Neurochem Res | volume = 35 | issue = 12 | pages = 1922–1932 | date = December 2010 | pmid = 20725780 | doi = 10.1007/s11064-010-0238-8 | url = }}{{cite journal | vauthors = Ekblom J, Oreland L, Chen K, Shih JC | title = Is there a "non-MAO" macromolecular target for L-deprenyl?: Studies on MAOB mutant mice | journal = Life Sci | volume = 63 | issue = 12 | pages = PL181–6 | date = 1998 | pmid = 9749831 | doi = 10.1016/s0024-3205(98)00370-1 | url = }}

MAEs require transport into monoaminergic neurons by monoamine transporters (MATs) like the dopamine transporter (DAT). Hence, they must be substrates of these transporters in order to exert their MAE effects. This may be due to the fact that the TAAR1 is located intracellularly within neurons. Transport by MATs into monoaminergic neurons is similarly required for the releasing effects of monoamine releasing agents (MRAs) like amphetamine. The TAAR1 may also be involved in the releasing effects of MRAs as with MAEs.{{cite book | vauthors = Wu R, Liu J, Li JX | title = Behavioral Pharmacology of Drug Abuse: Current Status | chapter = Trace amine-associated receptor 1 and drug abuse | series = Adv Pharmacol | volume = 93 | pages = 373–401 | date = 2022 | pmid = 35341572 | pmc = 9826737 | doi = 10.1016/bs.apha.2021.10.005 | isbn = 978-0-323-91526-7 | chapter-url = | quote = It is reported that methamphetamine (METH) interacts with TAAR1 and subsequently inhibits DA uptake, enhance DA efflux and induces DAT internalization, and these effects are dependent on TAAR1 (Xie & Miller, 2009). For example, METH-induced inhibition of DA uptake was observed in TAAR1 and DAT cotransfected cells and WT mouse and monkey striatal synaptosomes but not in DAT-only transfected cells or in striatal synaptosomes of TAAR1-KO mice (Xie & Miller, 2009). TAAR1 activation was enhanced by co-expression of monoamine transporters and this effect could be blocked by monoamine transporter antagonists (Xie & Miller, 2007; Xie et al., 2007). Furthermore, DA activation of TAAR1 induced C-FOS-luciferase expression only in the presence of DAT (Xie et al., 2007).}}{{cite journal | vauthors = Xie Z, Miller GM | title = A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain | journal = J Pharmacol Exp Ther | volume = 330 | issue = 1 | pages = 316–325 | date = July 2009 | pmid = 19364908 | pmc = 2700171 | doi = 10.1124/jpet.109.153775 | url = }}{{cite journal | vauthors = Lewin AH, Miller GM, Gilmour B | title = Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journal = Bioorg Med Chem | volume = 19 | issue = 23 | pages = 7044–7048 | date = December 2011 | pmid = 22037049 | pmc = 3236098 | doi = 10.1016/j.bmc.2011.10.007 | url = | quote = While our data suggest a role for TAAR1 in eliciting amphetamine-like stimulant effects, it must be borne in mind that the observed in vivo effects are likely to result from interaction with both TAAR1 and monoamine transporters. Thus it has been shown that the selective TAAR1 agonist RO5166017 fully prevented psychostimulant-induced and persistent hyperdopaminergia-related hyperactivity in mice.42 This effect was found to be DAT-independent, since suppression of hyperactivity was observed in DAT-KO mice.42 The collected information leads us to conclude that TAAR1 is a stereoselective binding site for amphetamine and that TAAR1 activation by amphetamine and its congeners may contribute to the stimulant properties of this class of compounds.}} It has been proposed that there may be two distinct binding sites on the TAAR1, one for MAEs and one for MRAs. MAEs are thought to induce action potential-dependent vesicular monoamine release via TAAR1 activation, whereas MRAs are thought to induce impulse-independent non-vesicular monoamine release via TAAR1 activation. However, there are conflicting findings with regard to the involvement of TAAR1 activation in the monoamine-releasing actions of MRAs, such as TAAR1 activation and signaling inhibiting the psychostimulant and reinforcing effects of MRAs, MRAs continuing to induce monoamine release in TAAR1 knockout mice,{{cite book | vauthors = Espinoza S, Gainetdinov RR | title=Taste and Smell | chapter=Neuronal Functions and Emerging Pharmacology of TAAR1 | series=Topics in Medicinal Chemistry | publisher=Springer International Publishing | publication-place=Cham | volume=23 | date=2014 | isbn=978-3-319-48925-4 | doi=10.1007/7355_2014_78 | pages=175–194}}{{cite journal | vauthors = Liu J, Wu R, Li JX | title = TAAR1 and Psychostimulant Addiction | journal = Cellular and Molecular Neurobiology | volume = 40 | issue = 2 | pages = 229–238 | date = March 2020 | pmid = 31974906 | pmc = 7845786 | doi = 10.1007/s10571-020-00792-8 }}{{cite journal | vauthors = Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC | title = Trace amine-associated receptor 1 modulates dopaminergic activity | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 324 | issue = 3 | pages = 948–956 | date = March 2008 | pmid = 18083911 | doi = 10.1124/jpet.107.132647 }}{{cite journal | vauthors = Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM | title = Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1 | journal = Pharmacology, Biochemistry, and Behavior | volume = 101 | issue = 2 | pages = 201–207 | date = April 2012 | pmid = 22079347 | pmc = 3288391 | doi = 10.1016/j.pbb.2011.10.025 }} and many MRAs, including most cathinones, being inactive as agonists of the human TAAR1.{{cite journal | vauthors = Kuropka P, Zawadzki M, Szpot P | title = A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse | journal = Hum Psychopharmacol | volume = 38 | issue = 3 | pages = e2866 | date = May 2023 | pmid = 36866677 | doi = 10.1002/hup.2866 | url = | quote = Another feature that distinguishes [substituted cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).}}{{cite journal | vauthors = Simmler LD, Liechti ME | title = Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 252 | issue = | pages = 143–164 | date = 2018 | pmid = 29633178 | doi = 10.1007/164_2018_113 | isbn = 978-3-030-10560-0 | url = | quote = The activation of human TAAR1 might diminish the effects of psychostimulation and intoxication arising from 7-APB effects on monoamine transporters (see 4.1.3. for more details). Affinity to mouse and rat TAAR1 has been shown for many psychostimulants, but species differences are common (Simmler et al. 2016). For example, [5-(2-aminopropyl)indole (5-IT)] and [4-methylamphetamine (4-MA)] bind and activate TAAR1 in the nanomolar range, but do not activate human TAAR1.}}{{cite journal | vauthors = Rickli A, Kolaczynska K, Hoener MC, Liechti ME | title = Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR | journal = Neurotoxicology | volume = 72 | issue = | pages = 95–100 | date = May 2019 | pmid = 30776375 | doi = 10.1016/j.neuro.2019.02.011 | bibcode = 2019NeuTx..72...95R }}

As with MRAs like amphetamine and monoamine reuptake inhibitors like methylphenidate, single acute doses of MAEs rapidly increase brain monoamine levels. However, MAEs have more limited impacts on brain monoamine levels compared to MRAs and monoamine reuptake inhibitors. In an in vivo rodent study, BPAP was found to maximally increase dopamine levels in the striatum by 44%, in the substantia nigra by 118%, and in the olfactory tubercle by 57%; norepinephrine levels in the locus coeruleus by 228%; and serotonin levels in the raphe nucleus by 166%.{{cite journal | vauthors = Knoll J, Yoneda F, Knoll B, Ohde H, Miklya I | title = (-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain | journal = Br J Pharmacol | volume = 128 | issue = 8 | pages = 1723–1732 | date = December 1999 | pmid = 10588928 | pmc = 1571822 | doi = 10.1038/sj.bjp.0702995 | url = }} The maximal impacts of other MAEs like selegiline on brain monoamine levels are similar. For comparison, the norepinephrine–dopamine releasing agent amphetamine increases dopamine levels in the striatum by 700 to 1,500% of baseline and norepinephrine levels in the prefrontal cortex by 400 to 450% of baseline.{{cite journal | vauthors = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present--a pharmacological and clinical perspective | journal = J Psychopharmacol | volume = 27 | issue = 6 | pages = 479–496 | date = June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 | url =}} However, there appears to be no dose–effect ceiling with this agent and it can maximally increase striatal dopamine levels by more than 5,000% of baseline at higher doses.{{cite journal | vauthors = Heal DJ, Smith SL, Kulkarni RS, Rowley HL | title = New perspectives from microdialysis studies in freely-moving, spontaneously hypertensive rats on the pharmacology of drugs for the treatment of ADHD | journal = Pharmacol Biochem Behav | volume = 90 | issue = 2 | pages = 184–197 | date = August 2008 | pmid = 18456311 | doi = 10.1016/j.pbb.2008.03.016 | url = }}{{cite conference | url = https://www.abstractsonline.com/pp8/#!/1820/presentation/12987 | title = The SH rat model of ADHD has profoundly different catecholaminergic responses to amphetamine's enantiomers compared with Sprague-Dawleys | vauthors = Cheetham SC, Kulkarni RS, Rowley HL, Heal DJ | date = 2007 | conference = Neuroscience 2007, San Diego, CA, Nov 3-7, 2007 | conference-url = https://www.abstractsonline.com/pp8/#!/1820 | publisher = Society for Neuroscience | archive-url = https://archive.today/20240727180222/https://www.abstractsonline.com/pp8/%23!/1820/presentation/12987 | archive-date = 27 July 2024 | quote = Both d- and l-[amphetamine (AMP)] evoked rapid increases in extraneuronal concentrations of [noradrenaline (NA)] and [dopamine (DA)] that reached a maximum 30 or 60 min after administration. However, the [spontaneously hypertensive rats (SHRs)] were much more responsive to AMP's enantiomers than the [Sprague-Dawleys (SDs)]. Thus, 3 mg/kg d-AMP produced a peak increase in [prefrontal cortex (PFC)] NA of 649 ± 87% (p<0.001) in SHRs compared with 198 ± 39% (p<0.05) in SDs; the corresponding figures for [striatal (STR)] DA were 4898 ± 1912% (p<0.001) versus 1606 ± 391% (p<0.001). At 9 mg/kg, l-AMP maximally increased NA efflux by 1069 ± 105% (p<0.001) in SHRs compared with 157 ± 24% (p<0.01) in SDs; the DA figures were 3294 ± 691% (p<0.001) versus 459 ± 107% (p<0.001).}} Monoamine reuptake inhibitors including methylphenidate, atomoxetine, bupropion, and vanoxerine (GBR-12909) also robustly increase brain monoamine levels in rodents, though the maximal impacts of these agents are much smaller (e.g., 5- to 10-fold lower) than those of releasers like amphetamine.

MAEs like PPAP and BPAP have been found to increase locomotor activity, increase stereotyped behavior, facilitate learning and retention, and produce antidepressant-like effects in rodent studies.{{cite journal | vauthors = Shimazu S, Takahata K, Katsuki H, Tsunekawa H, Tanigawa A, Yoneda F, Knoll J, Akaike A | title = (-)-1-(Benzofuran-2-yl)-2-propylaminopentane enhances locomotor activity in rats due to its ability to induce dopamine release | journal = Eur J Pharmacol | volume = 421 | issue = 3 | pages = 181–189 | date = June 2001 | pmid = 11516435 | doi = 10.1016/s0014-2999(01)01040-8 | url = }} In relation to these effects, they have been described as having psychostimulant-like effects. The locomotor stimulant effect of BPAP has been shown to be dependent on enhancement of dopaminergic signaling. In contrast to PPAP and BPAP, as well as in contrast to amphetamines, selegiline does not appear to stimulate locomotor activity and lacks psychostimulant-like effects in rodents.{{cite journal | vauthors = Timár J, Gyarmati Z, Barna L, Knoll B | title = Differences in some behavioural effects of deprenyl and amphetamine enantiomers in rats | journal = Physiol Behav | volume = 60 | issue = 2 | pages = 581–587 | date = August 1996 | pmid = 8840922 | doi = 10.1016/s0031-9384(96)80035-7 | url = }} Accordingly, selegiline has been reported to not activate the mesolimbic dopamine pathway in rodents.{{cite journal | vauthors = Gyarmati S, Hársing LG, Tekes K, Knoll J | title = Repeated administration of (-)deprenyl leaves the mesolimbic dopaminergic activity unchanged | journal = Acta Physiol Hung | volume = 75 Suppl | issue = | pages = 133–134 | date = 1990 | pmid = 2115226 | doi = | url = }}

Antagonists of MAEs are known. For example, 3-F-BPAP, a derivative of BPAP, antagonizes the MAE actions of BPAP. However, it does not antagonize the MAE actions of selegiline or PPAP. EPPTB, a TAAR1 antagonist, has been found to reverse the MAE actions of both BPAP and selegiline. Likewise, rasagiline has been found to reverse the MAE actions of selegiline and has been proposed as a possible TAAR1 antagonist.

József Knoll, the developer of the MAEs, was interviewed by David Healy in 2000 about his work and about MAEs.{{cite book | vauthors = Healy D |author-link1=David Healy (psychiatrist)| title=The Psychopharmacologists, Vol. III: Interviews |publisher=Arnold |location=London |year=2000 |pages=81–110 |doi=10.4324/9781003058892-3|isbn=978-0-340-76110-6 |chapter=The Psychopharmacology of Life and Death. Interview with Joseph Knoll. | chapter-url=https://books.google.com/books?id=NJEBEAAAQBAJ&pg=PT109}} In the interview, Healy asked Knoll the question of why MAEs should be preferred for increasing monoaminergic signaling and enhancing drive over other monoaminergic drugs, including monoamine releasing agents such as amphetamines, monoamine reuptake inhibitors, monoamine metabolism inhibitors, and direct monoamine receptor agonists. Knoll answered that other monoaminergic agents create an artificial, unphysiological, and abnormal situation in the brain that has substantial accompanying side effects and problems, for instance triggering of homeostatic compensation mechanisms. In contrast, Knoll maintained that MAEs simply augment normal and physiological monoaminergic signaling by increasing the amount of monoamine neurotransmitter released per action potential. He described this as very similar to how the brain situation-dependently regulates its own monoaminergic activity and stated that it is simply a matter of shifting the normal physiological range to allow for a higher level of activity and consequent behavioral performance. On the basis of these arguments, Knoll claimed that MAEs are theoretically better-tolerated, safer, and less tolerance-forming than other monoaminergic drugs.

An endogenous enhancer regulation system for monoaminergic neurons has been proposed to exist in which so-called enhancer substances can potentiate the action potential-evoked release of monoamine neurotransmitters in a variety of brain areas. This has also been referred to as the "mesencephalic enhancer regulation" system to emphasize the key importance of dopaminergic neurons and their modulation of behavior in this system. However, enhancer-sensitive neurons are also present outside of the mesencephalon (midbrain) and activity enhancers can affect noradrenergic and serotonergic neurons as well. Enhancer effects have even been observed in the peripheral nervous system. The enhancer regulation system has been theorized to play an important role in dynamically controlling innate and acquired drives and mediating age-related changes in goal-directed behavioral activity. The concept of this system was created and advanced by the developers of selegiline, including József Knoll and Ildikó Miklya. Endogenous enhancer substances like phenethylamine and tryptamine are known, but are of relatively low potency. The key endogenous actors in the enhancer regulation system have been hypothesized to be much more potent but have not been identified.

Rodents are much more behaviorally and motivationally active in the late developmental phase of life (2{{nbsp}}months) than in the early post-developmental phase (4{{nbsp}}months).{{cite journal | vauthors = Knoll J, Miklya I | title = Enhanced catecholaminergic and serotoninergic activity in rat brain from weaning to sexual maturity: rationale for prophylactic (-)deprenyl (selegiline) medication | journal = Life Sci | volume = 56 | issue = 8 | pages = 611–620 | date = 1995 | pmid = 7869839 | doi = 10.1016/0024-3205(94)00494-d | url = }} This has been specifically quantified with orienting-searching reflex activity induced by hunger. Male rats are weaned at about 3{{nbsp}}weeks of age and complete sexual development by 2{{nbsp}}months of age. Subsequent research found that brain monoamine release is much higher during the developmental phase (4{{nbsp}}weeks of age) compared to prior to weaning (2{{nbsp}}weeks of age) or following sexual maturity (16–32{{nbsp}}weeks of age). This has included dopamine release in the striatum, substantia nigra, and olfactory tubercle; norepinephrine release in the locus coeruleus; and serotonin release in the raphe nucleus. Serotonin release was 6- to 7-fold higher at 4{{nbsp}}weeks of age compared to 2{{nbsp}}weeks of age, whereas dopamine and norepinephrine release in their respective areas was around 2-fold higher relative to pre-weaning and post-sexual maturity. In addition, monoamine release progressively declines with age going from 4{{nbsp}}weeks to 32{{nbsp}}weeks. The higher behavioral activity of rodents at 2{{nbsp}}months of age compared to before or after this age has been attributed to greater activity of the brain catecholaminergic system at this time.{{cite journal | vauthors = Miklya I, Knoll B, Knoll J | title = An HPLC tracing of the enhancer regulation in selected discrete brain areas of food-deprived rats | journal = Life Sci | volume = 72 | issue = 25 | pages = 2923–2930 | date = May 2003 | pmid = 12697275 | doi = 10.1016/s0024-3205(03)00192-9 | url = }}

As previously described, brain monoamine release begins to rapidly decrease with sexual maturity in rodents. This suggests that sex hormones and the onset of their production may dampen brain monoamine release. Accordingly, brain monoamine release was found to be significantly higher in prepubertally castrated rats at 3{{nbsp}}months of age compared to non-castrated controls. In addition, treatment of 3-week-old prepubertal rats for 2{{nbsp}}weeks with exogenous sex hormones, including the androgen testosterone or the estrogen estrone, though not progesterone, significantly and rapidly reduced brain monoamine release relative to untreated controls.{{cite journal | vauthors = Knoll J, Miklya I, Knoll B, Dalló J | title = Sexual hormones terminate in the rat: the significantly enhanced catecholaminergic/serotoninergic tone in the brain characteristic to the post-weaning period | journal = Life Sci | volume = 67 | issue = 7 | pages = 765–773 | date = July 2000 | pmid = 10968406 | doi = 10.1016/s0024-3205(00)00671-8 | url = }} Similarly, sexual activity following sexual maturity substantially declines with age in both male rodents and humans. This is thought to be due to age-related decreased activity of the brain dopaminergic system.

It is known that brain levels of phenethylamine, a known endogenous enhancer substance, decline with age. This may be due to progressively increased levels of MAO-B with age. Decreased levels of phenethylamine may contribute to reduced activation of the enhancer regulation system and reduced brain catecholamine release with age. However, the key endogenous actors of the enhancer regulation system have been theorized to be more potent than phenethylamine but have yet to be identified. It has been hypothesized that highly potent enhancer substances may exist that may be able to rapidly modulate the activity of brain catecholaminergic neurons by as much as 5- to 10-fold to quickly control time-dependent motivational states.{{cite journal | vauthors = Knoll J | title = Memories of my 45 years in research | journal = Pharmacol Toxicol | volume = 75 | issue = 2 | pages = 65–72 | date = August 1994 | pmid = 7971740 | doi = 10.1111/j.1600-0773.1994.tb00326.x | url = }} However, such mediators remain speculative and have not been discovered or substantiated as of present.

Rodent studies have found that exogenous MAEs like selegiline and BPAP augment brain monoamine release, slow monoaminergic neurodegeneration, and help to preserve behavioral activity with age. As an example, selegiline has been found to augment sexual performance and delay its age-related decline in rodents.{{cite journal | vauthors = Knoll J, Yen TT, Miklya I | title = Sexually low performing male rats die earlier than their high performing peers and (-)deprenyl treatment eliminates this difference | journal = Life Sci | volume = 54 | issue = 15 | pages = 1047–1057 | date = 1994 | pmid = 8152326 | doi = 10.1016/0024-3205(94)00415-3 | url = }} It has been proposed that exogenous MAEs like selegiline might be able to modestly slow the age-related decay of brain monoamine release in humans, although such hypotheses have yet to be tested.{{cite book | last=Knoll | first=J. | title=How Selegiline ((-)-Deprenyl) Slows Brain Aging | publisher=Bentham Science Publishers | year=2012 | isbn=978-1-60805-470-1 | url=https://books.google.com/books?id=wV0NAgAAQBAJ | access-date=28 July 2024 | page=}}{{cite book | last=Knoll | first=J. | title=The Brain and Its Self: A Neurochemical Concept of the Innate and Acquired Drives | publisher=Springer Berlin Heidelberg | series=SpringerLink: Springer e-Books | year=2005 | isbn=978-3-540-27434-6 | url=https://books.google.com/books?id=L_CCw7agYIwC | access-date=28 July 2024 | page=}}

Selegiline is currently the only MAE without concomitant potent monoamine releasing agent actions that is available for medical use. It is also a selective MAO-B inhibitor and is used in the treatment of Parkinson's disease and depression. According to József Knoll, one of the original developers of selegiline, the CAE effects of selegiline may be more important than MAO-B inhibition in terms of its effectiveness for Parkinson's disease. This is consistent with clinical findings that selegiline may be more effective in the treatment of Parkinson's disease than rasagiline.{{cite journal | vauthors = Binde CD, Tvete IF, Gåsemyr J, Natvig B, Klemp M | title = A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson's disease | journal = Br J Clin Pharmacol | volume = 84 | issue = 9 | pages = 1917–1927 | date = September 2018 | pmid = 29847694 | pmc = 6089809 | doi = 10.1111/bcp.13651 | url = }}

Selective MAEs have been proposed for potential medical use in the treatment of a variety of conditions. These include psychiatric disorders like depression and attention deficit hyperactivity disorder (ADHD) as well as neurodegenerative diseases like Parkinson's disease and Alzheimer's disease.{{cite journal | vauthors = Gaszner P, Miklya I | title = The use of the synthetic enhancer substances (-)-deprenyl and (-)-BPAP in major depression | journal = Neuropsychopharmacol Hung | volume = 6 | issue = 4 | pages = 210–220 | date = December 2004 | pmid = 15825677 | doi = | url = }}{{cite journal | vauthors = Gaszner P, Miklya I | title = Major depression and the synthetic enhancer substances, (-)-deprenyl and R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 30 | issue = 1 | pages = 5–14 | date = January 2006 | pmid = 16023777 | doi = 10.1016/j.pnpbp.2005.06.004 | url = }} There has also been theoretical interest in MAEs as potential antiaging agents that might help to oppose age-related catecholaminergic neurodegeneration and prolong lifespan, though such ideas have not been tested. Benzofuranylpropylaminopentane (BPAP) in particular has been proposed for potential clinical development.{{cite journal | vauthors = Magyar K, Lengyel J, Bolehovszky A, Knoll B, Miklya I, Knoll J | title = The fate of (-)1-(benzofuran-2-yl)-2-propylaminopentane . HCl, (-)-BPAP, in rats, a potent enhancer of the impulse-evoked release of catecholamines and serotonin in the brain | journal = Eur J Drug Metab Pharmacokinet | volume = 27 | issue = 3 | pages = 157–161 | date = 2002 | pmid = 12365195 | doi = 10.1007/BF03190451 | url = }} However, no other MAEs besides selegiline have been developed for medical use as of present.

Amphetamine, methamphetamine, and likely other substituted amphetamines are MAEs, but their MAE effects are overshadowed and complicated by their concomitant potent monoamine releasing agent activities.

• Phenylethylamine
• Tryptamine
• Tyramine

• BPAP
• PPAP
• IPAP{{cite journal | vauthors = Yoneda F, Moto T, Sakae M, Ohde H, Knoll B, Miklya I, Knoll J | title = 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 | journal = Bioorg Med Chem | volume = 9 | issue = 5 | pages = 1197–212 | date = May 2001 | pmid = 11377178 | doi = 10.1016/s0968-0896(01)00002-5 | url = }}
• MPAP
• NPAP
• Deprenyl
• Selegiline (L-deprenyl)
• D-Deprenyl
• Desmethylselegiline
• 4-Fluorodeprenyl
• Amphetamine
• Dextroamphetamine
• Levoamphetamine
• Methamphetamine
• Dextromethamphetamine
• Levomethamphetamine

• 3-F-BPAP
• EPPTB
• Rasagiline

• Pro-motivational agent

{{Reflist}}

{{Monoaminergic activity enhancers}}

Category:Neurophysiology

Category:Selegiline

Category:Trace amines