dopamine releasing agent

No selective and robust DRAs are currently known.{{cite journal | vauthors = Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB | title = Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys | journal = J Pharmacol Exp Ther | volume = 320 | issue = 2 | pages = 627–636 | date = February 2007 | pmid = 17071819 | doi = 10.1124/jpet.106.107383 | url = | quote = As is commonly true for existing monoamine releasers, the potency of these compounds to release norepinephrine was similar to or higher than potency to release dopamine, and compounds with exclusive selectivity for dopamine or norepinephrine release are not yet available (Rothman et al., 2001). [...] Second, the present study documented optimal effects with releasers selective for dopamine/norepinephrine versus serotonin release; however, the degree to which the dopaminergic and/or noradrenergic effects of these drugs contributes to their profiles of behavioral effects remains to be determined. Releasers with selectivity for dopamine versus both norepinephrine and serotonin would help address this issue.}} The lack of known selective DRAs is related to the fact that it has proven extremely difficult to separate dopamine transporter (DAT) affinity from norepinephrine transporter (NET) affinity and retain releasing capability at the same time.{{cite journal | vauthors = Rothman RB, Blough BE, Baumann MH | title = Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions | journal = AAPS J | volume = 9 | issue = 1 | pages = E1–10 | date = January 2007 | pmid = 17408232 | pmc = 2751297 | doi = 10.1208/aapsj0901001 | url = | quote = Based in part on the above rationale, we sought to identify and characterize a non-amphetamine transporter substrate that would be a potent releaser of DA and 5-HT without affecting the release of NE. After an extensive evaluation of over 350 compounds, we found it virtually impossible to dissociate NE- and DA-releasing properties, perhaps because of phylogenetic similarities between NET and DAT.}} Despite evaluation of over 350{{nbsp}}compounds, it was reported in 2007 that it had been virtually impossible to dissociate norepinephrine and dopamine release. By 2014, still no selective DRAs had been identified, despite approximately 1,400{{nbsp}}compounds having been screened. Similarly, while moderately selective norepinephrine releasing agents (NRAs) are known (e.g., ~10- to 20-fold preference or norepinephrine over dopamine release),{{cite journal | vauthors = Kohut SJ, Jacobs DS, Rothman RB, Partilla JS, Bergman J, Blough BE | title = Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys | journal = Psychopharmacology (Berl) | volume = 234 | issue = 23–24 | pages = 3455–3465 | date = December 2017 | pmid = 28889212 | pmc = 5747253 | doi = 10.1007/s00213-017-4731-5 | url = | quote = In the present experiments, two monoamine releasers, [levomethamphetamine (l-MA)] and [D-phenylalaninol (PAL-329)], were shown to produce cocaine-like discriminative-stimulus effects in monkeys, suggesting that they meet the above criteria. One of these compounds, l-MA, also has been shown to serve as a positive reinforcer in rodents (Yokel and Pickens 1973) and monkeys (Winger et al 1994), further confirming the overlap with behavioral effects of cocaine. Both compounds also exhibit an approximately 15-fold greater potency in releasing NE than DA, which may be therapeutically advantageous. }} no highly selective NRAs had been identified. The inability to identify selective DRAs has been attributed to the strong phylogenetic similarities between the DAT and NET. Although no selective DRAs have been identified, selective SDRAs, albeit with concomitant serotonin receptor agonism, were described in 2014. SDRAs without known serotonin receptor agonism, such as BK-NM-AMT, were described by 2019.{{cite journal | vauthors = Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB | title = The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes | journal = Psychopharmacology (Berl) | volume = 236 | issue = 3 | pages = 915–924 | date = March 2019 | pmid = 30341459 | pmc = 6475490 | doi = 10.1007/s00213-018-5063-9 | url = }}{{cite patent | country = US | number = 20240335414 | invent1 = Matthew J. Baggott | invent2 = Sean Dalziel | assign = Tactogen Inc. | title=Specialized combinations for mental disorders or mental enhancement | url=https://patents.google.com/patent/US20240335414A1/ | pubdate = 10 October 2024 }}{{cite patent | country = WO | number = 2022061242 | inventor = Matthew Baggott | status = | title = Advantageous tryptamine compositions for mental disorders or enhancement | pubdate = 2023 March 24 | gdate = | fdate = 2021 September 20 | pridate = 2021 September 20 | assign1 = Tactogen | url = https://patents.google.com/patent/WO2022061242A1/}}

Although no selective DRAs are currently known, many non-selective releasing agents of both dopamine and norepinephrine (norepinephrine–dopamine releasing agents or NDRAs) and of serotonin, norepinephrine, and dopamine (serotonin–norepinephrine–dopamine releasing agents or SNDRAs) are known.{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = European Journal of Pharmacology | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 }}{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }} Examples of major NDRAs include the psychostimulants amphetamine and methamphetamine, while an example of an SNDRA is the entactogen methylenedioxymethamphetamine (MDMA). These drugs are frequently used for recreational purposes and encountered as drugs of abuse. DRAs, including NDRAs and theoretically also selective DRAs, have medical utility in the treatment of attention deficit hyperactivity disorder (ADHD). SDRAs, for instance 5-chloro-αMT, are less common and are not selective for dopamine release, but have also been developed.{{cite journal |vauthors=Blough BE, Landavazo A, Partilla JS, et al. | title = Alpha-ethyltryptamines as dual dopamine-serotonin releasers | journal = Bioorganic & Medicinal Chemistry Letters | volume = 24 | issue = 19 | pages = 4754–4758 |date=October 2014 | pmid = 25193229 | doi = 10.1016/j.bmcl.2014.07.062 | pmc=4211607}}{{cite journal |vauthors=Banks ML, Bauer CT, Blough BE, et al. | title = Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys | journal = Experimental and Clinical Psychopharmacology | volume = 22 | issue = 3 | pages = 274–284 |date=June 2014 | pmid = 24796848 | doi = 10.1037/a0036595 | url = http://content.apa.org/journals/pha/22/3/274 | pmc=4067459}} Tryptamines like 5-chloro-αMT are the only known releaser scaffold that consistently release dopamine more potently than norepinephrine.

Selective DRAs might have different clinical effects in the treatment of attention deficit hyperactivity disorder (ADHD) than the NDRAs like amphetamines and norepinephrine–dopamine reuptake inhibitors (NDRIs) like methylphenidate that are currently used.{{cite book | vauthors = Heal DJ, Smith SL, Findling RL | title = Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment | chapter = ADHD: current and future therapeutics | series = Current Topics in Behavioral Neurosciences | volume = 9 | issue = | pages = 361–90 | date = 2012 | pmid = 21487953 | doi = 10.1007/7854_2011_125 | isbn = 978-3-642-24611-1 | chapter-url = | quote = When predicting the likely efficacy and safety of new therapeutic approaches in ADHD, the knowledge gained from existing drugs can be helpful. The pharmacological characteristics of the most effective drugs for treating ADHD, the stimulants, are summarised below and in Table 3: 1. These drugs produce large and rapid increases in the synaptic concentration of catecholamines in the PFC. 2. There is no obvious ceiling on the magnitude of their effect on catecholamine efflux. 3. The most efficacious ADHD drugs also enhance dopaminergic neurotransmission in sub-cortical brain regions. However, some caveats have to be taken into consideration. For example, lack of information in the public domain indicates that drugs that are selective dopamine releasing agents, or noradrenaline reuptake inhibitors with the pharmacological characteristics of methylphenidate, have not been evaluated as potential ADHD therapies. Hence, it is impossible to know whether sub-cortical dopamine efflux is a critical component of maximal efficacy in an ADHD medication, or alternatively, whether a drug with a selective noradrenergic mechanism that is as powerful as methylphenidate or amphetamine could rival the efficacy of the stimulants.}} For example, they might have improved therapeutic selectivity by reducing or eliminating the cardiovascular and sympathomimetic side effects of NDRAs.{{cite journal | vauthors = Sotomayor-Zárate R, Jara P, Araos P, Vinet R, Quiroz G, Renard GM, Espinosa P, Hurtado-Guzmán C, Moya PR, Iturriaga-Vásquez P, Gysling K, Reyes-Parada M | title = Improving amphetamine therapeutic selectivity: N,N-dimethyl-MTA has dopaminergic effects and does not produce aortic contraction | journal = Basic Clin Pharmacol Toxicol | volume = 114 | issue = 5 | pages = 395–399 | date = May 2014 | pmid = 24314229 | doi = 10.1111/bcpt.12168 | url = }}

Amphetamines like dextroamphetamine and dextromethamphetamine are fairly balanced NDRAs but release norepinephrine about 2- to 3-fold more potently than dopamine.{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | url = }}{{cite book | vauthors = Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB | chapter = Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes | title = Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc | series = NIDA Res Monogr | volume = 180 | pages = 1–476 (252) | date = 1999 | pmid = 11680410 | doi = | url = https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261 | quote = RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.}} However, other studies found that dextroamphetamine and dextromethamphetamine were roughly equipotent or slightly favored dopamine in terms of norepinephrine versus dopamine release.{{cite journal | vauthors = Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV | title = The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue | journal = Neuropsychopharmacology | volume = 37 | issue = 5 | pages = 1192–1203 | date = April 2012 | pmid = 22169943 | pmc = 3306880 | doi = 10.1038/npp.2011.304 | url = }} A number of potentially more well-balanced NDRAs, including levomethcathinone (l-MC), 3-chloroamphetamine (3-CA; PAL-304),{{cite journal | vauthors = Blough BE, Landavazo A, Partilla JS, Baumann MH, Decker AM, Page KM, Rothman RB | title = Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics | journal = ACS Med Chem Lett | volume = 5 | issue = 6 | pages = 623–627 | date = June 2014 | pmid = 24944732 | pmc = 4060932 | doi = 10.1021/ml500113s | url = }} 3-chloromethcathinone (3-CMC; clophedrone; PAL-434),{{cite journal | vauthors = Kohut SJ, Fivel PA, Blough BE, Rothman RB, Mello NK | title = Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys | journal = Int J Neuropsychopharmacol | volume = 16 | issue = 9 | pages = 1985–1998 | date = October 2013 | pmid = 23768644 | doi = 10.1017/S146114571300059X | url = }} and 2-phenylmorpholine (2-PM; PAL-632), are known, and all appear to be roughly equipotent in inducing dopamine versus norepinephrine release. A few NDRAs, including cis-4-methylaminorex (cis-4-MAR),{{cite journal | vauthors = Maier J, Mayer FP, Brandt SD, Sitte HH | title = DARK Classics in Chemical Neuroscience: Aminorex Analogues | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2484–2502 | date = October 2018 | pmid = 30269490 | pmc = 6287711 | doi = 10.1021/acschemneuro.8b00415 | url = }}{{cite journal | vauthors = Brandt SD, Baumann MH, Partilla JS, Kavanagh PV, Power JD, Talbot B, Twamley B, Mahony O, O'Brien J, Elliott SP, Archer RP, Patrick J, Singh K, Dempster NM, Cosbey SH | title = Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni') | journal = Drug Testing and Analysis | volume = 6 | issue = 7–8 | pages = 684–695 | year = 2014 | pmid = 24841869 | pmc = 4128571 | doi = 10.1002/dta.1668 }} 3-chlorophenmetrazine (3-CPM; PAL-594),{{cite journal | last1=Namjoshi | first1=Ojas A. | last2=Decker | first2=Ann M. | last3=Landavazo | first3=Antonio | last4=Partilla | first4=John S. | last5=Baumann | first5=Michael H. | last6=Rothman | first6=Richard B. | last7=Blough | first7=Bruce E. | title=Chemical modifications to alter monoamine releasing activity of phenmetrazine analogs as potential treatments of stimulant addiction | journal=Drug and Alcohol Dependence | volume=146 | date=2015 | doi=10.1016/j.drugalcdep.2014.09.502 | page=e48}}{{cite patent | country = US | number = 20130203752 | url=https://www.google.com/patents/US20130203752 | title= Phenylmorpholines and analogues thereof | pubdate = 8 August 2013 | gdate = 11 April 2017 | inventor = Blough BE, Rothman R, Landavazo A, Page KM, Decker AM | assign1 = National Institutes of Health, U.S. Department of Health and Human Services }} and naphthylmetrazine (PAL-704), appear to release dopamine about 2- to 3-fold more potently than norepinephrine, and hence may be among the most dopamine-selective NDRAs known.

Pemoline, which is structurally related to the aminorex drugs, is a stimulant used to treat ADHD which is said to act as a selective DRI and DRA, but it is said to only weakly stimulate dopamine release.{{cite journal | vauthors = Patrick KS, Markowitz JS | title = Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder | journal = Human Psychopharmacology: Clinical and Experimental | date = November 1997 | volume = 12 | issue = 6 | pages = 527–546 | issn = 0885-6222 | eissn = 1099-1077 | doi = 10.1002/(SICI)1099-1077(199711/12)12:6<527::AID-HUP932>3.0.CO;2-U | pmid = | s2cid = 144548631 | url = }}{{cite journal | vauthors = Nishino S, Mignot E | title = Pharmacological aspects of human and canine narcolepsy | journal = Prog Neurobiol | volume = 52 | issue = 1 | pages = 27–78 | date = May 1997 | pmid = 9185233 | doi = 10.1016/s0301-0082(96)00070-6 | s2cid = 31839355 | url = | doi-access = free }}{{cite web|title=Cylert (Pemoline)|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/016832s022_017703s018lbl.pdf|publisher=FDA|access-date=15 February 2014|date=December 2002|archive-date=4 March 2016|archive-url=https://web.archive.org/web/20160304002256/http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/016832s022_017703s018lbl.pdf|url-status=live}} There is reportedly some, albeit mixed, in-vitro evidence that the antidepressant and modestly selective DRI amineptine may, in addition to inhibiting the reuptake of dopamine, selectively induce the presynaptic release of dopamine without affecting release of norepinephrine or serotonin.{{cite book|author=J. K. Aronson|title=Meyler's Side Effects of Psychiatric Drugs|url=https://books.google.com/books?id=AmYFTSO8jCkC&pg=PA29|year=2009|publisher=Elsevier|isbn=978-0-444-53266-4|pages=29–}}{{cite journal|last1=Ceci|first1=A.|last2=Garattini|first2=S.|last3=Gobbi|first3=M.|last4=Mennini|first4=T.|title=Effect of long term amineptine treatment on pre- and postsynaptic mechanisms in rat brain|journal=British Journal of Pharmacology|volume=88|issue=1|year=1986|pages=269–275|issn=0007-1188|doi=10.1111/j.1476-5381.1986.tb09495.x|pmid=3708219|pmc=1917102}}{{cite journal|last1=Bonnet|first1=J. -J.|last2=Chagraoui|first2=A.|last3=Protais|first3=P.|last4=Costentin|first4=J.|title=Interactions of amineptine with the neuronal dopamine uptake system: Neurochemicalin vitro and in vivo studies|journal=Journal of Neural Transmission|volume=69|issue=3–4|year=1987|pages=211–220|issn=0300-9564|doi=10.1007/BF01244342|pmid=3625193 |s2cid=9886698 }} However, amineptine is larger than the known small structural size limit of monoamine releasing agents, suggesting that it may not in fact be a DRA.

Although no definite selective DRAs have been described, one possible exception is 2-fluoromethcathinone (2-FMC). It has an {{Abbrlink|EC₅₀|half-maximal effective concentration}} for dopamine release of 48.7{{nbsp}}nM but induces only 85% release of norepinephrine at a concentration of 10{{nbsp}}μM. For comparison, the {{Abbr|EC₅₀|half-maximal effective concentration}} values of the NDRA methcathinone are 49.9{{nbsp}}nM for dopamine release and 22.4{{nbsp}}nM for norepinephrine release and it induces 100% release of norepinephrine at a concentration of 10{{nbsp}}μM. Hence, compared to methcathinone, 2-FMC appears to be relatively more selective or efficacious for induction of dopamine release over norepinephrine release. In any case, the {{Abbr|EC₅₀|half-maximal effective concentration}} of 2-FMC for induction of norepinephrine release does not seem to be available. Moreover, in another instance, the related drug 3-methoxymethcathinone (3-MeOMC) released only 68% norepinephrine at 10{{nbsp}}μM, yet an {{Abbr|EC₅₀|half-maximal effective concentration}} value of the drug of 111{{nbsp}}nM for induction of norepinephrine release was provided in another publication.{{cite web | last=Shalabi | first=Abdelrahman R. | title=Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters | website=VCU Scholars Compass | date=14 December 2017 | url=https://scholarscompass.vcu.edu/etd/5176/ | access-date=24 November 2024}}{{cite journal | vauthors = Walther D, Shalabi AR, Baumann MH, Glennon RA | title = Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents | journal = ACS Chem Neurosci | volume = 10 | issue = 1 | pages = 740–745 | date = January 2019 | pmid = 30354055 | pmc = 8269283 | doi = 10.1021/acschemneuro.8b00524 | url = }}

{{Main|Monoamine releasing agent#Mechanism of action}}

• Monoamine releasing agent
• Norepinephrine–dopamine releasing agent
• Serotonin–dopamine releasing agent
• Serotonin–norepinephrine–dopamine releasing agent
• Norepinephrine releasing agent
• Serotonin releasing agent

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• {{Commons category-inline|Dopamine releasing agents}}

{{Monoamine releasing agents}}