عامل إطلاق مونوامين
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1 2 3 4 5 6 7 8 9  Heal DJ، Smith SL، Gosden J، Nutt DJ (يونيو 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. ج. 27 ع. 6: 479–496. DOI:10.1177/0269881113482532. PMC:3666194. PMID:23539642. مؤرشف من الأصل في 2024-12-15. اطلع عليه بتاريخ 2025-01-19. Although the pharmacological effect of amphetamine is predominantly mediated by monoamine release, this mechanism is complemented by reuptake inhibition [...] that combine additively or synergistically to augment synaptic monoamine concentrations. The description of amphetamine as a 'monoamine reuptake inhibitor' often causes some confusion, and the difference between the mechanisms of amphetamine, which is a competitive reuptake transport substrate, and classical reuptake inhibitors is illustrated in Figure 3. [...] d-Amphetamine is generally accepted to be a weak dopamine reuptake inhibitor with a Ki value of ~100 nM, a moderately potent inhibitor of noradrenaline reuptake (Ki = 40–50 nM) and a very weak inhibitor of 5-HT reuptake (Ki = 1.4-3.8 µM). [...] the efficacy of amphetamine relative to other indirect monoamine agonists, for example classical reuptake inhibitors, can only be estimated from in vivo experiments. [...] [d- and l-Amphetamine] dose-dependently increased the extracellular concentrations of noradrenaline in the prefrontal cortex (PFC) and dopamine in the striatum. The pharmacodynamics of their effects are typical of those reported for monoamine releasing agents, i.e. a fast onset of action with peak increases of noradrenaline and dopamine efflux occurring at 30–45 min, large effects (400–450% of baseline for noradrenaline and 700–1500% of baseline for dopamine), with a relatively rapid decline after the maximum (Figure 4). [...] the magnitude of the increases produced by amphetamine's isomers are greater than those reported for classical reuptake inhibitors such as atomoxetine or bupropion, and there is no dose-effect ceiling to amphetamine's actions [...] The primary action of amphetamine is to increase synaptic concentrations of monoamine neurotransmitters, thereby indirectly enhancing noradrenergic, dopaminergic neurotransmission in the CNS.
1 2 3 4 5 6 7 8 9 10 11 12  Rothman RB، Baumann MH (أكتوبر 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. ج. 479 ع. 1–3: 23–40. DOI:10.1016/j.ejphar.2003.08.054. PMID:14612135. مؤرشف من الأصل في 2024-06-13. اطلع عليه بتاريخ 2025-01-19.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25  Rothman RB، Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. ج. 6 ع. 17: 1845–1859. DOI:10.2174/156802606778249766. PMID:17017961. اطلع عليه بتاريخ 2025-01-19.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56  Blough B (يوليو 2008). "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. ص. 305–320. ISBN:978-0-470-11790-3. OCLC:181862653. OL:18589888W. اطلع عليه بتاريخ 2025-01-19. {{استشهاد بكتاب}}: الوسيط غير المعروف |مسار-الفصل= تم تجاهله (مساعدة)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45  Reith ME، Blough BE، Hong WC، Jones KT، Schmitt KC، Baumann MH، Partilla JS، Rothman RB، Katz JL (فبراير 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. ج. 147: 1–19. DOI:10.1016/j.drugalcdep.2014.12.005. PMC:4297708. PMID:25548026. مؤرشف من الأصل في 2024-07-12. اطلع عليه بتاريخ 2025-01-19. Converging lines of evidence have solidified the notion that DA releasers are substrates of the transporter and once translocated, they reverse the normal direction of transporter flux to evoke release of endogenous neurotransmitters. The nature of this reversal is not well understood, but the entire process is primarily transporter-dependent and requires elevated intracellular sodium concentrations, phosphorylation of DAT, and possible involvement of transporter oligomers (Khoshbouei et al., 2003, 2004; Sitte and Freissmuth, 2010). [...] A library of approximately 1400 phenethylamine compounds (PAL compounds) has been screened using these protocols. Among the active compounds,the smaller DAT ligands were found to be DA releasers while the sterically larger compounds were DAT uptake inhibitors. [...] Generic pharmacophore for biogenic amine transporter ligands. Note that transportable substrate ligands exhibit size constraints defined by the red circle. Functional groups attached to the nitrogen, α-carbon or phenyl ring that extend beyond the "edge" of the pharmacophore will generate partial substrates, transporter blockers or be inactive. [...] phenmetrazine was found to be completely inactive at VMAT2 indicating that a direct interaction of the releaser with VMAT2 is not required for inducing neurotransmitter efflux into the extracellular space (Partilla et al., 2006). Phentermine and benzylpiperazine were also found in the same study to lack VMAT2 activity (Table 5).
1 2 3 4 5 6 7 8  Schmitt KC، Rothman RB، Reith ME (يوليو 2013). "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". The Journal of Pharmacology and Experimental Therapeutics. ج. 346 ع. 1: 2–10. DOI:10.1124/jpet.111.191056. PMC:3684841. PMID:23568856. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19.
1 2 3 4 5  Heal DJ، Gosden J، Smith SL (ديسمبر 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology. ج. 87: 19–40. DOI:10.1016/j.neuropharm.2014.06.012. PMID:24953830. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19.
1 2 3 4 5  Shimazu S، Miklya I (مايو 2004). "Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives". Progress in Neuro-Psychopharmacology & Biological Psychiatry. ج. 28 ع. 3: 421–427. DOI:10.1016/j.pnpbp.2003.11.016. PMID:15093948. S2CID:37564231. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19.
1 2 3 4 5  Knoll J (أغسطس 2003). "Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives". Neurochemical Research. ج. 28 ع. 8: 1275–1297. DOI:10.1023/a:1024224311289. PMID:12834268. اطلع عليه بتاريخ 2025-01-19.
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31  Blough BE، Landavazo A، Partilla JS، Decker AM، Page KM، Baumann MH، Rothman RB (أكتوبر 2014). "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters. ج. 24 ع. 19: 4754–4758. DOI:10.1016/j.bmcl.2014.07.062. PMC:4211607. PMID:25193229. اطلع عليه بتاريخ 2025-01-19.
1 2 3 4 5 6 7  Banks ML، Bauer CT، Blough BE، Rothman RB، Partilla JS، Baumann MH، Negus SS (يونيو 2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology. ج. 22 ع. 3: 274–284. DOI:10.1037/a0036595. PMC:4067459. PMID:24796848. اطلع عليه بتاريخ 2025-01-19.
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  Reith ME، Gnegy ME (2020). "Molecular Mechanisms of Amphetamines". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. ج. 258: 265–297. DOI:10.1007/164_2019_251. ISBN:978-3-030-33678-3. PMID:31286212. اطلع عليه بتاريخ 2025-01-19. Despite the knowledge that amphetamine is a substrate for the DAT and NET, questions still remain as to the physiological mechanism of amphetamine action. [...] At lower doses, amphetamine preferentially releases a newly synthesized pool of DA. [...] DA stores will not be depleted by the AMPT in these short time frames, leading to the conclusion that newly synthesized DA is a principal substrate for amphetamine-stimulated DA efflux. [...] Controversy has surrounded the role of VMAT2 and synaptic vesicles in the mechanism of amphetamine action. [...] Undoubtedly vesicles contribute strongly to the maximal DA released by amphetamine, although VMAT2 is not absolutely required for amphetamine to release DA from nerve terminals (Pifl et al. 1995; Fon et al. 1997; Wang et al. 1997; Patel et al. 2003). [...] Recently, a new model of amphetamine action has been formulated that proposes that amphetamine elevates tonic DA (non-exocytotic) signaling through reverse transport and depleting vesicular stores, but activates phasic DA signaling by enhancing vesicular DA release from the readily releasable pool (Covey et al. 2013). These conclusions were drawn from experiments using fast-scan cyclic voltammetry in either freely moving or anesthetized rats (Avelar et al. 2013; Daberkow et al. 2013). Again, one must strongly consider the dose of amphetamine in interpretation of these actions (Calipari and Ferris 2013).
1 2 3 4 5 6 7 8 9 10  Sulzer D، Sonders MS، Poulsen NW، Galli A (أبريل 2005). "Mechanisms of neurotransmitter release by amphetamines: a review". Prog Neurobiol. ج. 75 ع. 6: 406–433. DOI:10.1016/j.pneurobio.2005.04.003. PMID:15955613. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19. While the sine qua non property of AMPH at monoamine transporters is the promotion of monoamine release via reverse transport, there are yet profound mysteries in understanding how this works. It is additionally clear that AMPH is an uptake blocker as well as a releaser, and differentiating between elevating extracellular monoamines by reverse transport or uptake blockade can be difficult. Of course, the many AMPH derivatives and different transporters maintain different combinatorial properties, an important topic beyond the range of this article. [...] The mechanism of how reverse transport occurs is unknown, and a very old issue of how reserpine can inhibit uptake but not halt reverse transport remains opaque.
1 2 3 4  Sitte HH، Freissmuth M (يناير 2015). "Amphetamines, new psychoactive drugs and the monoamine transporter cycle". Trends Pharmacol Sci. ج. 36 ع. 1: 41–50. DOI:10.1016/j.tips.2014.11.006. PMC:4502921. PMID:25542076. مؤرشف من الأصل في 2025-01-17. اطلع عليه بتاريخ 2025-01-19. [...] most amphetamines are [monoamine transporter] substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. [...] Amphetamines also bind to the trace amine receptors TAR1, [...] TAR1 is not activated by all psychoactive amphetamines (p-chloroamphetamine, for instance, is inactive); stimulation of TAR1 actually reduces dopamine release and thus decreases sensitivity to amphetamine [18,19]. [...] amphetamines are taken up by plasma-membrane monoamine transporters as exogenous substrates [31]. Accordingly, they inhibit the physiological monoamine reuptake in a competitive manner [36]. As a consequence of both amphetamine-induced reverse transport and inhibition of reuptake, the synaptic monoamine concentration increases, which in turn activates post- and presynaptic receptors [37]. The activation of postsynaptic receptors propagates the signal and contributes to the biological response. Stimulation of presynaptic autoreceptors decreases the quantal release of monoamines upon excitatory inputs; [...]
1 2 3 4 5  Kuropka P، Zawadzki M، Szpot P (مايو 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol. ج. 38 ع. 3: e2866. DOI:10.1002/hup.2866. PMID:36866677. مؤرشف من الأصل في 2023-04-03. اطلع عليه بتاريخ 2025-01-19. An interesting neurochemical issue is the interaction between compounds acting as blockers and substrates. [...] Substrates (e.g. mephedrone) use MAT proteins to release neurotransmitters, while inhibitors (e.g. [MDPV]) prevent the transport of any compounds through MATs. It follows that simultaneous use of a substrate and a blocker should result in an antagonistic mechanism that lowers the mutual potency. Paradoxically, MDPV and mephedrone occur together in mixtures, and in addition they reinforce each other's effects, resulting in very strong stimulation. Simultaneous use of both SCs is reported by users, and studies in rodents involving simultaneous administration of the drugs have shown a significant increase in locomotor activity and additive effect compared to administering these drugs alone (Allen et al., 2019; Benturquia et al., 2019). [...] The explanation for this phenomenon can be found in the action of organic cation transporter (OCT) proteins. OCTs are a family of proteins responsible for endothelial transport of small, organic, hydrophilic, and positively charged molecules, including neurotransmitters and xenobiotics (Couroussé & Gautron, 2015). OCT3 is a protein present in the dopaminergic regions of the central nervous system, where it promotes DA reuptake when it is inhibited for high affinity transporters (DAT) (Couroussé & Gautron, 2015). Monoamines can also be released by OCTs. [...] Ex vivo studies on superior cervical ganglia cells enriched in NET and OCT3 showed that in the presence of MDPV blocking MAT proteins, mephedrone causes neurotransmitter efflux through OCT3, which is insensitive to the inhibitory effects of MDPV. The release of monoamines through OCT3, a low‐affinity transporter, presumably explains the paradoxical synergistic effects of inhibitors and substrates (Mayer et al., 2019). [...] Another feature that distinguishes [synthetic 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). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 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).
1 2  Partilla JS، Dempsey AG، Nagpal AS، Blough BE، Baumann MH، Rothman RB (أكتوبر 2006). "Interaction of amphetamines and related compounds at the vesicular monoamine transporter". J Pharmacol Exp Ther. ج. 319 ع. 1: 237–246. DOI:10.1124/jpet.106.103622. PMID:16835371. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19. A number of test drugs displayed no activity in the [3H]dopamine uptake inhibition assay (Table 1). For example, (+)- phenmetrazine and (–)-phenmetrazine, the major metabolites of phendimetrazine (Rothman et al., 2002), were essentially inactive. [...] In contrast, other amphetamine-type agents, such as phentermine, phenmetrazine, and 1-benzylpiperazine, are potent releasers of neuronal dopamine (Baumann et al., 2000, 2005; Rothman et al., 2002), but they are inactive at VMAT2. Agents such as these may prove to be valuable control compounds for determining the importance of vesicular release for the in vivo actions of amphetamine-type agents.
1 2 3 4  Oeri HE (مايو 2021). "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". J Psychopharmacol. ج. 35 ع. 5: 512–536. DOI:10.1177/0269881120920420. PMC:8155739. PMID:32909493. مؤرشف من الأصل في 2024-11-11. اطلع عليه بتاريخ 2025-01-19.
1 2  Pifl C، Reither H، Hornykiewicz O (مايو 2015). "The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter". Eur J Pharmacol. ج. 755: 119–126. DOI:10.1016/j.ejphar.2015.03.004. PMID:25771452. مؤرشف من الأصل في 2025-01-20. اطلع عليه بتاريخ 2025-01-19.
↑  Cozzi NV، Sievert MK، Shulgin AT، Jacob P، Ruoho AE (سبتمبر 1999). "Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines". Eur J Pharmacol. ج. 381 ع. 1: 63–69. DOI:10.1016/s0014-2999(99)00538-5. PMID:10528135. مؤرشف من الأصل في 2024-12-29. اطلع عليه بتاريخ 2025-01-19.
↑  Wimalasena K (يوليو 2011). "Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry". Med Res Rev. ج. 31 ع. 4: 483–519. DOI:10.1002/med.20187. PMC:3019297. PMID:20135628. مؤرشف من الأصل في 2024-02-17. اطلع عليه بتاريخ 2025-01-19.
↑  Simmler، Linda D. (2018). "Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones". Synthetic Cathinones. Current Topics in Neurotoxicity. Cham: Springer International Publishing. ج. 12. ص. 97–115. DOI:10.1007/978-3-319-78707-7_6. ISBN:978-3-319-78706-0. اطلع عليه بتاريخ 2025-01-19. While the determination of drug effects at the isolated target (i.e., DAT, NET, and SERT) can characterize the direct drug action at the target protein, other physiological components can also contribute significantly to the overall effect of the drug. It has been proposed that transporter-mediated, drug-induced efflux of neurotransmitter occurs through effects on the vesicular monoamine transporter 2 (VMAT2), depleting neurotransmitter from the vesicles into the cytosol (Nickell et al. 2014). Accordingly, full assessment of release would require testing the effects of a drug on the membrane transporters (SERT, DAT, and NET) and the effects of a drug at VMAT2. Alternatively, a more physiological system, such as synaptosomes or brain slices, could be used. However, reverse transport can also occur in cell lines that only express the plasma membrane transporters but not VMAT2 (Eshleman et al. 2013; Scholze et al. 2000) and in synaptosomes when VMAT2 is inhibited (Rothman et al. 2001).
1 2 3 4 5 6 7  Halberstadt AL، Brandt SD، Walther D، Baumann MH (مارس 2019). "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology (Berl). ج. 236 ع. 3: 989–999. DOI:10.1007/s00213-019-05207-1. PMC:6848746. PMID:30904940. اطلع عليه بتاريخ 2025-01-19. In contrast to assay systems involving non-neuronal cells transfected with transporter proteins, synaptosomes possess all of the cellular machinery necessary for neurotransmitter synthesis, release, metabolism, and reuptake. Synaptosomes, however, do not model all of the effects of amphetamine-type agents because the use of reserpine removes any contribution of the vesicular monoamine transporter VMAT2 (SLC18A2) to the release process. In addition to acting as a substrate for plasma membrane monoamine transporters, amphetamine also binds to VMAT, resulting in the redistribution of monoamines from vesicular stores to the cytoplasm (Sulzer et al. 1995; Partilla et al. 2006; Freyberg et al. 2016). Although transporter substrates can induce monoamine release in the absence of VMAT binding (Fon et al. 1997), it is important to recognize that 2-aminoindans may have effects in intact nerve terminals that are not fully replicated in synaptosomes. Follow-up studies will be conducted to evaluate whether 2-aminoindans are capable of interacting with VMAT.
1 2 3  Sulzer D، Cragg SJ، Rice ME (أغسطس 2016). "Striatal dopamine neurotransmission: regulation of release and uptake". Basal Ganglia. ج. 6 ع. 3: 123–148. DOI:10.1016/j.baga.2016.02.001. PMC:4850498. PMID:27141430. مؤرشف من الأصل في 2025-01-15. اطلع عليه بتاريخ 2025-01-19. 2.2.1. DAT regulation by psychostimulants [...] Considerable evidence supports a role for DAT substrates, like amphetamine, in inducing DAT internalization in vivo and in vitro, thus decreasing DA uptake [390–395]. [...] While several kinases are involved in the regulation of DAT, PKC is by far the most thoroughly investigated [388,403]. PKC activation induces DAT internalization [393,404–406] although the mechanism of PKC activation by DAT substrates remains largely unknown [388,389,403,407,408]
1 2 3 4 5 6 7  Docherty JR، Alsufyani HA (أغسطس 2021). "Pharmacology of Drugs Used as Stimulants". J Clin Pharmacol. 61 Suppl 2: S53–S69. DOI:10.1002/jcph.1918. PMID:34396557. مؤرشف من الأصل في 2024-10-09. اطلع عليه بتاريخ 2025-01-19. Release by an indirect agonist is termed reverse transport and may require buildup of neurotransmitter in the nerve cytoplasm [...] Stimulants can act to stimulate presynaptic (CNS) or prejunctional (periphery) receptors for the neurotransmitter on nerve terminals to control release from those endings. These receptors are usually inhibitory and are marked as I (either NE, DA, or 5-HT inhibitory receptor) in Figure 1 and as α2 (inhibitory α2- adrenoceptor) in Figure 2, respectively. For instance, α2-adrenoceptors are present as autoreceptors on noradrenergic nerves and mediate an inhibition of NE release both in the periphery and CNS (see Figures 1 and 2).71 [...] Stimulants can act to stimulate, either directly or indirectly via increased release of the monoamine neurotransmitter, receptors for the neurotransmitter on nerves or effector cells situated postsynaptically/postjunctionally to the monoaminergic neuron. [...] Receptor-mediated actions of amphetamine and other amphetamine derivatives [...] may involve trace amine-associated receptors (TAARs) at which amphetamine and MDMA also have significant potency.85–87 Many stimulants have potency at the rat TAAR1 in the micromolar range but tend to be about 5 to 10 times less potent at the human TAAR1, [...] Activation of the TAAR1 receptor causes inhibition of dopaminergic transmission in the mesocorticolimbic system, and TAAR1 agonists attenuated psychostimulant abuse-related behaviors.89 It is likely that TAARs contribute to the actions of specific stimulants to modulate dopaminergic, serotonergic, and glutamate signaling,90 and drugs acting on the TAAR1 may have therapeutic potential.91 In the periphery, stimulants such as MDMA and cathinone produce vasoconstriction, part of which may involve TAARs, although only relatively high concentrations produced vascular contractions resistant to a cocktail of monoamine antagonist drugs.86