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Monoaminergic activity enhancer

(Redirected from Catecholaminergic activity enhancers)

Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of drugs that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system.[5] MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release.[1][6] That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse.[1][6]

Monoaminergic activity enhancer
Drug class
Selegiline, the prototypical MAE.
Class identifiers
SynonymsMAE; Monoamine activity enhancer; Catecholaminergic activity enhancer; Catecholamine activity enhancer; CAE; Dopaminergic activity enhancer; Dopamine activity enhancer; DAE; Serotonergic activity enhancer; Serotonin activity enhancer; SAE; Catecholaminergic/serotonergic activity enhancer; CAE/SAE
UseDepression, Parkinson's disease, other conditions
Mode of actionEnhancement of the action potential-mediated release of monoamine neurotransmitters
Mechanism of actionPossibly TAAR1 agonism[1][2][3][4]
Chemical classPhenethylamines, tryptamines, benzofurans, others
Legal status
In Wikidata

MAEs have been shown to significantly enhance nerve impulse-mediated dopamine release in the striatum, substantia nigra, and olfactory tubercle; norepinephrine release from the locus coeruleus; and/or serotonin release from the raphe nucleus in rodent studies.[7] Some MAEs are selective for effects on some of these neurotransmitters but not on others.[1][7] The maximal impacts of MAEs on brain monoamine levels are more modest than with monoamine releasing agents like amphetamine and monoamine reuptake inhibitors like methylphenidate.[7][8] MAEs have a peculiar and characteristic bimodal concentration–response relationship, with two bell-shaped curves of MAE activity across tested concentration ranges.[1][9][7][4][10] Hence, there is a restricted concentration range for optimal pharmacodynamic activity.[9]

Endogenous MAEs include certain trace amines like β-phenylethylamine and tryptamine, while synthetic MAEs include certain phenethylamine and tryptamine derivatives like selegiline, phenylpropylaminopentane (PPAP), benzofuranylpropylaminopentane (BPAP), and indolylpropylaminopentane (IPAP).[1][7][3] Although this was originally not known, the actions of MAEs may be mediated by agonism of the trace amine-associated receptor 1 (TAAR1).[1][2][3][4] Antagonists of MAEs, like EPPTB (a known TAAR1 antagonist), 3-F-BPAP, and rasagiline, have been identified.[3][4][7]

Endogenous monoaminergic activity enhancers

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A few endogenous MAEs have been identified, including the trace amines β-phenylethylamine (PEA), tyramine, and tryptamine.[1][11] At a concentration of 16 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.[7][1] Conversely, tryptamine has been found to act as a MAE for serotonin (3.6-fold increase) at a concentration of 1.3 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 μΜ (1.3 × 10-5 M) in the rat brainstem in vitro.[7][9][1] It is apparent that tryptamine at a concentration of 1.3 μΜ is a much more effective MAE of serotonin than is β-phenylethylamine at a concentration of 16 μM.[7][9] 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.[1] It has been suggested that these selectivities may indicate the existence of multiple MAE receptors for these compounds.[7][9] Tyramine has been shown to act as a MAE of norepinephrine, dopamine, and serotonin in the rat brainstem in vitro similarly to β-phenylethylamine.[11] β-Phenylethylamine and tyramine additionally act as potent monoamine releasing agents of norepinephrine and dopamine at higher concentrations.[12][11] The MAE and monoamine releasing agent actions of these compounds are mechanistically distinct and they have been referred to as "mixed-acting" monoaminergic potentiators.[11]

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.[7][9][13][14] For example, BPAP has been found to have peak effects at a concentration of 10-14 M (femtomolar to picomolar range).[5][7][9][13][12][14] 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.[5][7][9][13]

Monoaminergic activity enhancing drugs

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β-Phenylethylamine, tryptamine, and tyramine when administered to animals are ineffective as MAEs in vivo due to very rapid breakdown by monoamine oxidase (MAO).[1][11] 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.[15][16][17][18] Tyramine, unlike β-phenylethylamine and tryptamine, is unable to cross the blood–brain barrier, which additionally limits its capacity for centrally mediated effects.[1][19]

Selegiline (L-deprenyl) (a phenylethylamine derivative) is used as an antiparkinsonian agent and antidepressant and exhibits CAE effects independent of its monoamine oxidase inhibition.[12] It has been shown to enhance both impulse-evoked norepinephrine and dopamine release.[4] Selegiline shows a bimodal concentration–response relationship in terms of its CAE actions for dopamine activity in the striatum.[4] Besides enhancing catecholaminergic activity, it has additionally been found to decrease serotonergic activity.[20] Selegiline's metabolite desmethylselegiline has also been found to be active as a CAE.[21][22] Aside from selegiline and its metabolites, D-deprenyl is a CAE, with slightly lower potency than selegiline.[20] By extension to selegiline and D-deprenyl, the racemic form, deprenyl, is a CAE.[20] A halogenated analogue of deprenyl, 4-fluorodeprenyl, has been found to act as a CAE as well.[20]

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.[5][23][3][20] Levomethamphetamine, levoamphetamine, and dextroamphetamine are all similarly potent as CAEs and compared to selegiline, but are substantially more potent as CAEs than dextromethamphetamine.[20] Besides acting as CAEs, levomethamphetamine and dextromethamphetamine diminish serotonergic activity, similarly to selegiline, whereas levoamphetamine and dextroamphetamine do not do so.[20]

Phenylpropylaminopentane (PPAP) is a CAE for norepinephrine and dopamine that was derived from selegiline and is a phenethylamine derivative.[24] In contrast to selegiline, it lacks monoamine oxidase inhibition and hence is much more selective in its actions.[25] Indolylpropylaminopentane (IPAP) is a MAE for serotonin, norepinephrine, and dopamine that was derived from PPAP and is a tryptamine derivative.[7][3][26] It shows some selectivity for serotonin, with its maximal impact on this neurotransmitter occurring at 10-fold lower concentrations than for norepinephrine or dopamine.[3][26] Benzofuranylpropylaminopentane (BPAP) is a MAE for serotonin, norepinephrine, and dopamine that was derived from PPAP and is related to tryptamine.[1][27] It is about 130 times more potent in its MAE actions than selegiline.[1] Similarly to selegiline, BPAP shows a bimodal concentration–response relationship in its MAE effects.[1][9][10]

In contrast to selegiline, rasagiline and its metabolite (R)-1-aminoindan do not have MAE actions.[4][21] Similarly, SU-11739 (AGN-1133; J-508), the N-methylated analogue of rasagiline and a closer analogue of selegiline, does not have MAE actions.[21]

Mechanism of action

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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).[1][2] 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.[3][28][29] In addition, recent findings have suggested that known synthetic MAEs like BPAP and selegiline may exert their effects via TAAR1 activation.[3][4] This was evidenced by the TAAR1 antagonist EPPTB reversing their MAE effects, among other findings.[3][4] 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.[30][14][31]

MAEs require transport into monoaminergic neurons by monoamine transporters (MATs) like the dopamine transporter (DAT).[3] Hence, they must be substrates of these transporters in order to exert their MAE effects.[3] This may be due to the fact that the TAAR1 is located intracellularly within neurons.[3] Transport by MATs into monoaminergic neurons is similarly required for the releasing effects of monoamine releasing agents (MRAs) like amphetamine.[3] The TAAR1 may also be involved in the releasing effects of MRAs as with MAEs.[3][32][33][34] It has been proposed that there may be two distinct binding sites on the TAAR1, one for MAEs and one for MRAs.[3] 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.[3] 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,[28][35][36][37][38] MRAs continuing to induce monoamine release in TAAR1 knockout mice,[28][36][35][37][38] and many MRAs, including most cathinones, being inactive as agonists of the human TAAR1.[39][40][29][41]

As with MRAs like amphetamine and monoamine reuptake inhibitors like methylphenidate, single acute doses of MAEs rapidly increase brain monoamine levels.[7][8] However, MAEs have more limited impacts on brain monoamine levels compared to MRAs and monoamine reuptake inhibitors.[7] 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%.[7][14] The maximal impacts of other MAEs like selegiline on brain monoamine levels are similar.[7] 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.[42] 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.[42][8][43] 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.[42][8]

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.[24][44] In relation to these effects, they have been described as having psychostimulant-like effects.[24][44] The locomotor stimulant effect of BPAP has been shown to be dependent on enhancement of dopaminergic signaling.[44] 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.[45] Accordingly, selegiline has been reported to not activate the mesolimbic dopamine pathway in rodents.[46][17]

Antagonists

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Antagonists of MAEs are known.[7] For example, 3-F-BPAP, a derivative of BPAP, antagonizes the MAE actions of BPAP.[7] However, it does not antagonize the MAE actions of selegiline or PPAP.[7] EPPTB, a TAAR1 antagonist, has been found to reverse the MAE actions of both BPAP and selegiline.[3][4] Likewise, rasagiline has been found to reverse the MAE actions of selegiline and has been proposed as a possible TAAR1 antagonist.[4]

Monoaminergic activity enhancers versus other monoaminergic drugs

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József Knoll, the developer of the MAEs, was interviewed by David Healy in 2000 about his work and about MAEs.[47] 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.[47] 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.[47] In contrast, Knoll maintained that MAEs simply augment normal and physiological monoaminergic signaling by increasing the amount of monoamine neurotransmitter released per action potential.[47] 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.[47] On the basis of these arguments, Knoll claimed that MAEs are theoretically better-tolerated, safer, and less tolerance-forming than other monoaminergic drugs.[47]

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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.[9][7] 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.[9][7] However, enhancer-sensitive neurons are also present outside of the mesencephalon (midbrain) and activity enhancers can affect noradrenergic and serotonergic neurons as well.[7][9] Enhancer effects have even been observed in the peripheral nervous system.[1] 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.[9][7] The concept of this system was created and advanced by the developers of selegiline, including József Knoll and Ildikó Miklya.[12] Endogenous enhancer substances like phenethylamine and tryptamine are known, but are of relatively low potency.[9][7] The key endogenous actors in the enhancer regulation system have been hypothesized to be much more potent but have not been identified.[9][7]

Rodents are much more behaviorally and motivationally active in the late developmental phase of life (2 months) than in the early post-developmental phase (4 months).[7][12][48] This has been specifically quantified with orienting-searching reflex activity induced by hunger.[7][48] Male rats are weaned at about 3 weeks of age and complete sexual development by 2 months of age.[7][48] Subsequent research found that brain monoamine release is much higher during the developmental phase (4 weeks of age) compared to prior to weaning (2 weeks of age) or following sexual maturity (16–32 weeks of age).[7][12][48] 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.[7][12][48] Serotonin release was 6- to 7-fold higher at 4 weeks of age compared to 2 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.[7][48] In addition, monoamine release progressively declines with age going from 4 weeks to 32 weeks.[48] The higher behavioral activity of rodents at 2 months of age compared to before or after this age has been attributed to greater activity of the brain catecholaminergic system at this time.[7][12][48][49]

As previously described, brain monoamine release begins to rapidly decrease with sexual maturity in rodents.[7][12] This suggests that sex hormones and the onset of their production may dampen brain monoamine release.[7][12] Accordingly, brain monoamine release was found to be significantly higher in prepubertally castrated rats at 3 months of age compared to non-castrated controls.[7][50] In addition, treatment of 3-week-old prepubertal rats for 2 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.[7][12][50] Similarly, sexual activity following sexual maturity substantially declines with age in both male rodents and humans.[7] This is thought to be due to age-related decreased activity of the brain dopaminergic system.[7]

It is known that brain levels of phenethylamine, a known endogenous enhancer substance, decline with age.[7] This may be due to progressively increased levels of MAO-B with age.[7] Decreased levels of phenethylamine may contribute to reduced activation of the enhancer regulation system and reduced brain catecholamine release with age.[9] 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.[9][7] 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.[51][11] However, such mediators remain speculative and have not been discovered or substantiated as of present.[51][11][12][1][7]

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.[7][12][23][48] As an example, selegiline has been found to augment sexual performance and delay its age-related decline in rodents.[7][52] 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.[9][51][12][53][54]

Medical use

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Selegiline is currently the only MAE without concomitant potent monoamine releasing agent actions that is available for medical use.[7] It is also a selective MAO-B inhibitor and is used in the treatment of Parkinson's disease and depression.[7][12] 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.[7] This is consistent with clinical findings that selegiline may be more effective in the treatment of Parkinson's disease than rasagiline.[12][4][55]

Selective MAEs have been proposed for potential medical use in the treatment of a variety of conditions.[1][9][56][13][24] 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.[1][9][56][13][24] 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.[12] Benzofuranylpropylaminopentane (BPAP) in particular has been proposed for potential clinical development.[1][5][57] However, no other MAEs besides selegiline have been developed for medical use as of present.[5][7][12]

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.[12][5][13]

List of monoaminergic activity enhancers

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Endogenous

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Synthetic

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Antagonists

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See also

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References

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  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x Shimazu, Seiichiro; Miklya, Ildikó (2004-05-01). "Pharmacological studies with endogenous enhancer substances: β-phenylethylamine, tryptamine, and their synthetic derivatives". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 28 (3): 421–427. doi:10.1016/j.pnpbp.2003.11.016. ISSN 0278-5846. PMID 15093948. S2CID 37564231.
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  26. ^ a b c Yoneda F, Moto T, Sakae M, Ohde H, Knoll B, Miklya I, Knoll J (May 2001). "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): 1197–212. doi:10.1016/s0968-0896(01)00002-5. PMID 11377178.
  27. ^ Magyar, Kálmán; Lengyel, Joseph; Bolehovszky, Andrea; Knoll, Bertha; Miklya, Iidikó; Knoll, Joseph (2002-09-01). "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". European Journal of Drug Metabolism and Pharmacokinetics. 27 (3): 157–161. doi:10.1007/BF03190451. ISSN 2107-0180. PMID 12365195. S2CID 30618267.
  28. ^ a b c Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
  29. ^ a b Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID 26791601.
  30. ^ Magyar K, Szende B, Jenei V, Tábi T, Pálfi M, Szöko E (December 2010). "R-deprenyl: pharmacological spectrum of its activity". Neurochem Res. 35 (12): 1922–1932. doi:10.1007/s11064-010-0238-8. PMID 20725780.
  31. ^ Ekblom J, Oreland L, Chen K, Shih JC (1998). "Is there a "non-MAO" macromolecular target for L-deprenyl?: Studies on MAOB mutant mice". Life Sci. 63 (12): PL181–6. doi:10.1016/s0024-3205(98)00370-1. PMID 9749831.
  32. ^ Wu R, Liu J, Li JX (2022). "Trace amine-associated receptor 1 and drug abuse". Adv Pharmacol. 93: 373–401. doi:10.1016/bs.apha.2021.10.005. PMC 9826737. PMID 35341572. 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).
  33. ^ Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". J Pharmacol Exp Ther. 330 (1): 316–325. doi:10.1124/jpet.109.153775. PMC 2700171. PMID 19364908.
  34. ^ Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorg Med Chem. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC 3236098. PMID 22037049. 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.
  35. ^ a b Liu J, Wu R, Li JX (March 2020). "TAAR1 and Psychostimulant Addiction". Cellular and Molecular Neurobiology. 40 (2): 229–238. doi:10.1007/s10571-020-00792-8. PMC 7845786. PMID 31974906.
  36. ^ a b Espinoza S, Gainetdinov RR (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Topics in Medicinal Chemistry. Vol. 23. Cham: Springer International Publishing. pp. 175–194. doi:10.1007/7355_2014_78. ISBN 978-3-319-48925-4.
  37. ^ a b Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC (March 2008). "Trace amine-associated receptor 1 modulates dopaminergic activity". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 948–956. doi:10.1124/jpet.107.132647. PMID 18083911.
  38. ^ a b Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM (April 2012). "Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1". Pharmacology, Biochemistry, and Behavior. 101 (2): 201–207. doi:10.1016/j.pbb.2011.10.025. PMC 3288391. PMID 22079347.
  39. ^ Kuropka P, Zawadzki M, Szpot P (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol. 38 (3): e2866. doi:10.1002/hup.2866. PMID 36866677. 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).
  40. ^ Simmler LD, Liechti ME (2018). "Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances". Handb Exp Pharmacol. 252: 143–164. doi:10.1007/164_2018_113. PMID 29633178. 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.
  41. ^ Rickli A, Kolaczynska K, Hoener MC, Liechti ME (May 2019). "Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR". Neurotoxicology. 72: 95–100. Bibcode:2019NeuTx..72...95R. doi:10.1016/j.neuro.2019.02.011. PMID 30776375.
  42. ^ a b c Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". J Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.
  43. ^ Cheetham SC, Kulkarni RS, Rowley HL, Heal DJ (2007). The SH rat model of ADHD has profoundly different catecholaminergic responses to amphetamine's enantiomers compared with Sprague-Dawleys. Neuroscience 2007, San Diego, CA, Nov 3-7, 2007. Society for Neuroscience. Archived from the original on 27 July 2024. 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).
  44. ^ a b c Shimazu S, Takahata K, Katsuki H, Tsunekawa H, Tanigawa A, Yoneda F, Knoll J, Akaike A (June 2001). "(-)-1-(Benzofuran-2-yl)-2-propylaminopentane enhances locomotor activity in rats due to its ability to induce dopamine release". Eur J Pharmacol. 421 (3): 181–189. doi:10.1016/s0014-2999(01)01040-8. PMID 11516435.
  45. ^ Timár J, Gyarmati Z, Barna L, Knoll B (August 1996). "Differences in some behavioural effects of deprenyl and amphetamine enantiomers in rats". Physiol Behav. 60 (2): 581–587. doi:10.1016/s0031-9384(96)80035-7. PMID 8840922.
  46. ^ Gyarmati S, Hársing LG, Tekes K, Knoll J (1990). "Repeated administration of (-)deprenyl leaves the mesolimbic dopaminergic activity unchanged". Acta Physiol Hung. 75 Suppl: 133–134. PMID 2115226.
  47. ^ a b c d e f Healy D (2000). "The Psychopharmacology of Life and Death. Interview with Joseph Knoll.". The Psychopharmacologists, Vol. III: Interviews. London: Arnold. pp. 81–110. doi:10.4324/9781003058892-3. ISBN 978-0-340-76110-6.
  48. ^ a b c d e f g h i Knoll J, Miklya I (1995). "Enhanced catecholaminergic and serotoninergic activity in rat brain from weaning to sexual maturity: rationale for prophylactic (-)deprenyl (selegiline) medication". Life Sci. 56 (8): 611–620. doi:10.1016/0024-3205(94)00494-d. PMID 7869839.
  49. ^ Miklya I, Knoll B, Knoll J (May 2003). "An HPLC tracing of the enhancer regulation in selected discrete brain areas of food-deprived rats". Life Sci. 72 (25): 2923–2930. doi:10.1016/s0024-3205(03)00192-9. PMID 12697275.
  50. ^ a b Knoll J, Miklya I, Knoll B, Dalló J (July 2000). "Sexual hormones terminate in the rat: the significantly enhanced catecholaminergic/serotoninergic tone in the brain characteristic to the post-weaning period". Life Sci. 67 (7): 765–773. doi:10.1016/s0024-3205(00)00671-8. PMID 10968406.
  51. ^ a b c Knoll J (August 1994). "Memories of my 45 years in research". Pharmacol Toxicol. 75 (2): 65–72. doi:10.1111/j.1600-0773.1994.tb00326.x. PMID 7971740.
  52. ^ Knoll J, Yen TT, Miklya I (1994). "Sexually low performing male rats die earlier than their high performing peers and (-)deprenyl treatment eliminates this difference". Life Sci. 54 (15): 1047–1057. doi:10.1016/0024-3205(94)00415-3. PMID 8152326.
  53. ^ Knoll, J. (2012). How Selegiline ((-)-Deprenyl) Slows Brain Aging. Bentham Science Publishers. ISBN 978-1-60805-470-1. Retrieved 28 July 2024.
  54. ^ Knoll, J. (2005). The Brain and Its Self: A Neurochemical Concept of the Innate and Acquired Drives. SpringerLink: Springer e-Books. Springer Berlin Heidelberg. ISBN 978-3-540-27434-6. Retrieved 28 July 2024.
  55. ^ Binde CD, Tvete IF, Gåsemyr J, Natvig B, Klemp M (September 2018). "A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson's disease". Br J Clin Pharmacol. 84 (9): 1917–1927. doi:10.1111/bcp.13651. PMC 6089809. PMID 29847694.
  56. ^ a b Gaszner P, Miklya I (December 2004). "The use of the synthetic enhancer substances (-)-deprenyl and (-)-BPAP in major depression". Neuropsychopharmacol Hung. 6 (4): 210–220. PMID 15825677.
  57. ^ Magyar K, Lengyel J, Bolehovszky A, Knoll B, Miklya I, Knoll J (2002). "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". Eur J Drug Metab Pharmacokinet. 27 (3): 157–161. doi:10.1007/BF03190451. PMID 12365195.


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