Norepinephrine releasing agent

NRAs, frequently as norepinephrine–dopamine releasing agents (NDRAs) rather than as selective NRAs, are used for a variety of clinical indications including the following:{{cite journal | vauthors = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present--a pharmacological and clinical perspective | journal = Journal of Psychopharmacology | volume = 27 | issue = 6 | pages = 479–496 | date = June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 }}{{cite journal | vauthors = Rasmussen N | title = Amphetamine-Type Stimulants: The Early History of Their Medical and Non-Medical Uses | journal = Int Rev Neurobiol | volume = 120 | issue = | pages = 9–25 | date = 2015 | pmid = 26070751 | doi = 10.1016/bs.irn.2015.02.001 | url = }}

• For the treatment of attention deficit hyperactivity disorder (ADHD) — e.g., amphetamine, dextroamphetamine, levoamphetamine, lisdexamfetamine, methamphetamine{{cite journal | vauthors = Heal DJ, Cheetham SC, Smith SL | title = The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety | journal = Neuropharmacology | volume = 57 | issue = 7–8 | pages = 608–618 | date = December 2009 | pmid = 19761781 | doi = 10.1016/j.neuropharm.2009.08.020 | url = }}
• As anorectics in the treatment of obesity and binge-eating disorder — e.g., amphetamine, lisdexamfetamine, phentermine, benzphetamine, phenmetrazine, aminorex{{cite journal | vauthors = Heal DJ, Smith SL | title = Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology | journal = J Psychopharmacol | volume = 36 | issue = 6 | pages = 680–703 | date = June 2022 | pmid = 34318734 | pmc = 9150143 | doi = 10.1177/02698811211032475 | url = }}
• As wakefulness-promoting agents in the treatment of narcolepsy — e.g., amphetamine, methamphetamine{{cite book | last1=Nishino | first1=Seiji | last2=Kotorii | first2=Nozomu | title=Narcolepsy | chapter=Overview of Management of Narcolepsy | publisher=Springer International Publishing | publication-place=Cham | date=2016 | isbn=978-3-319-23738-1 | doi=10.1007/978-3-319-23739-8_21 | pages=285–305}}{{cite book | last1=Nishino | first1=Seiji | last2=Kotorii | first2=Nozomu | title=Narcolepsy | chapter=Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics | publisher=Springer International Publishing | publication-place=Cham | date=2016 | isbn=978-3-319-23738-1 | doi=10.1007/978-3-319-23739-8_22 | pages=307–329}}
• As nasal decongestants and bronchodilators — e.g., levomethamphetamine, propylhexedrine, ephedrine, pseudoephedrine, phenylpropanolamine{{cite journal | vauthors = Aaron CK | title = Sympathomimetics | journal = Emerg Med Clin North Am | volume = 8 | issue = 3 | pages = 513–526 | date = August 1990 | pmid = 2201518 | doi = 10.1016/S0733-8627(20)30256-X| url = }}{{cite journal | vauthors = Hendeles L | title = Selecting a decongestant | journal = Pharmacotherapy | volume = 13 | issue = 6 Pt 2 | pages = 129S–134S; discussion 143S–146S | date = 1993 | pmid = 7507590 | doi = 10.1002/j.1875-9114.1993.tb02781.x| url = }}{{cite journal | vauthors = Barkholtz HM, Hadzima R, Miles A | title = Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature | journal = ACS Pharmacol Transl Sci | volume = 6 | issue = 7 | pages = 914–924 | date = July 2023 | pmid = 37470013 | pmc = 10353062 | doi = 10.1021/acsptsci.3c00019 | url = }}
• Miscellaneous – e.g., amantadine{{cite journal | vauthors = Wanka L, Iqbal K, Schreiner PR | title = The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives | journal = Chem Rev | volume = 113 | issue = 5 | pages = 3516–3604 | date = May 2013 | pmid = 23432396 | pmc = 3650105 | doi = 10.1021/cr100264t | url = }}{{cite journal | vauthors = Sommerauer C, Rebernik P, Reither H, Nanoff C, Pifl C | title = The noradrenaline transporter as site of action for the anti-Parkinson drug amantadine | journal = Neuropharmacology | volume = 62 | issue = 4 | pages = 1708–1716 | date = March 2012 | pmid = 22155208 | doi = 10.1016/j.neuropharm.2011.11.017 | url = }}

They are also used as recreational drugs, though this is typically reserved only for those that also induce the release of dopamine and/or serotonin, for instance amphetamine, methamphetamine, MDMA, mephedrone, 4-methylaminorex, and MDAI, among others.{{cite journal | vauthors = Schmitt KC, Reith ME | title = Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse | journal = Ann N Y Acad Sci | volume = 1187 | issue = | pages = 316–340 | date = February 2010 | pmid = 20201860 | doi = 10.1111/j.1749-6632.2009.05148.x | url = }}{{cite journal | vauthors = Meyer MR | title = New psychoactive substances: an overview on recent publications on their toxicodynamics and toxicokinetics | journal = Arch Toxicol | volume = 90 | issue = 10 | pages = 2421–2444 | date = October 2016 | pmid = 27665567 | doi = 10.1007/s00204-016-1812-x | bibcode = 2016ArTox..90.2421M | url = }}{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken [NJ] | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}{{Cite journal | vauthors = Gavai AK, Bouzembrak Y, van den Bulk LM, Liu N, van Overbeeke LF, van den Heuvel LJ, Mol H, Marvin HJ |date= December 2021 |title=Artificial intelligence to detect unknown stimulants from scientific literature and media reports |journal=Food Control |volume=130 |pages=108360 |doi=10.1016/j.foodcont.2021.108360 |issn=0956-7135|doi-access=free }}

Cathine and cathinone are NRAs found naturally in Catha edulis.{{cite journal | vauthors = Costa VM, Grando LG, Milandri E, Nardi J, Teixeira P, Mladěnka P, Remião F | title = Natural Sympathomimetic Drugs: From Pharmacology to Toxicology | journal = Biomolecules | volume = 12 | issue = 12 | date = November 2022 | page = 1793 | pmid = 36551221 | pmc = 9775352 | doi = 10.3390/biom12121793 | doi-access = free | url = }}{{cite journal | vauthors = Rothman RB, Baumann MH | title = Targeted screening for biogenic amine transporters: potential applications for natural products | journal = Life Sci | volume = 78 | issue = 5 | pages = 512–518 | date = December 2005 | pmid = 16202429 | doi = 10.1016/j.lfs.2005.09.001 | url = }} Ephedrine and pseudoephedrine are also found naturally in Ephedra sinica.{{cite journal | vauthors = Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA | title = In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates | journal = J Pharmacol Exp Ther | volume = 307 | issue = 1 | pages = 138–145 | date = October 2003 | pmid = 12954796 | doi = 10.1124/jpet.103.053975 | url = }} Both of these plants are used medicinally (and recreationally as well regarding the former). The endogenous trace amines phenethylamine and tyramine are NRAs found in many animals, including humans.{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}

Selective NRAs include ephedrine, pseudoephedrine, phenylpropanolamine, levomethamphetamine, and D-phenylalaninol.{{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. }} These drugs also release dopamine to a much lesser extent however (e.g., ~10- to 20-fold less potently). No highly selective NRAs are currently known.{{cite thesis | vauthors = Bauer CT | title=Determinants of Abuse-Related Effects of Monoamine Releasers in Rats | website=VCU Scholars Compass | date=5 July 2014 | doi=10.25772/AN08-SZ65 | url=https://scholarscompass.vcu.edu/etd/522/ | access-date=24 November 2024 | quote = Another potential determinant for increased abuse potential of [monoamine releasers (MARs)] is selectivity for [dopamine (DA)] versus [norepinephrine (NE)]. [...] amphetamine and other abused monoamine releasers have slightly (2 to 3x) higher potency to release NE than DA (Rothman et al., 2001). [...] ephedrine (a 19-fold NE-selective releaser) has been shown to maintain self-administration in monkeys (Anderson et al., 2001) and substitute for amphetamine (Young et al., 1998) and methamphetamine (Bondareva et al., 2002) in drug discrimination studies in rats. [...] This leads to the hypothesis that NE release is another determinant of the abuse-related effects produce by MARs; however, the role of DA vs. NE selectivity has been difficult to investigate further due to a lack of drugs that possess significant selectivity for DA or NE relative to the other catecholamine. [...] Unfortunately, compounds with low potency to release [serotonin (5HT)] and variable potencies to release DA vs. NE do not exist, [...] }} Among the most selective known NRAs is ephedrine, which had about 19-fold higher potency for inducing norepinephrine release over dopamine release in one study.{{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 = }} Levomethamphetamine has shown about 15-fold higher potency in inducing norepinephrine release over dopamine release. D-Phenylalaninol has 13-fold higher potency in inducing norepinephrine release over dopamine release. In contrast to levomethamphetamine, levoamphetamine is an NDRA, with only about 3-fold preference for inducing norepinephrine release over dopamine release in one study (versus dextroamphetamine being roughly equipotent on norepinephrine and dopamine release in the same study). NRAs play a significant role in treating ADHD, obesity, narcolepsy, and as sympathomimetics by enhancing adrenergic signaling.{{cite journal | last1=Ilipilla | first1=Geeta | last2=Arnold | first2=L. Eugene | title=The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium | journal=Expert Opinion on Pharmacotherapy | volume=25 | issue=8 | date=23 May 2024 | issn=1465-6566 | doi=10.1080/14656566.2024.2369197 | doi-access=free | pages=945–956| pmid=38900676 }}

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

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

{{Reflist|30em}}

• {{Commonscatinline|Norepinephrine releasing agents}}

{{Monoamine releasing agents}}