Norepinephrine releasing agent

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Ephedrine, one of the most well-known selective NRAs. Ephedrine v2.svg
Ephedrine, one of the most well-known selective NRAs.

A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into the synapse. [1] [2] This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine therefore an increase in adrenergic neurotransmission. [1] [2] [3] [4]

Contents

A closely related type of drug is a norepinephrine reuptake inhibitor (NRI), for instance reboxetine. [5] [6] Another class of drugs that stimulates adrenergic activity is the adrenergic receptor agonist class. [7]

Uses and examples

NRAs, frequently as norepinephrine–dopamine releasing agents (NDRAs) rather than as selective NRAs, are used for a variety of clinical indications including the following: [1] [2] [8] [9]

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. [19] [20] [21] [22]

Cathine and cathinone are NRAs found naturally in Catha edulis . [23] [24] Ephedrine and pseudoephedrine are also found naturally in Ephedra sinica . [23] [24] [25] Both of these plants are used medicinally (and recreationally as well regarding the former). [23] [24] [25] The endogenous trace amines phenethylamine and tyramine are NRAs found in many animals, including humans. [26] [1] [2]

Selective NRAs include ephedrine, pseudoephedrine, phenylpropanolamine, levomethamphetamine, and D-phenylalaninol. [1] [2] [25] [27] These drugs also release dopamine to a much lesser extent however (e.g., ~10- to 20-fold less potently). [1] [2] [25] [27] No highly selective NRAs are currently known. [28] 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. [28] [29] Levomethamphetamine has shown about 15-fold higher potency in inducing norepinephrine release over dopamine release. [27] [29] D-Phenylalaninol has 13-fold higher potency in inducing norepinephrine release over dopamine release. [27] 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). [21] NRAs play a significant role in treating ADHD, obesity, narcolepsy, and as sympathomimetics by enhancing adrenergic signaling. [1] [2] [8] [30]

Mechanism of action

See also

References

  1. 1 2 3 4 5 6 7 Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
  2. 1 2 3 4 5 6 7 Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961.
  3. ↑ Parker K, Brunton L, Goodman LS, Lazo JS, Gilman A (2006). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11 ed.). New York: McGraw-Hill. ISBN   0-07-142280-3. Archived from the original on 2011-11-18. Retrieved 2011-06-26.
  4. ↑ Foye W, Lemke T, Williams D (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. ISBN   978-0-7817-6879-5 . Retrieved 7 December 2024.
  5. ↑ N Maiti S, P Kamalesh Babu R (2006). "Norepinephrine Reuptake Inhibitors for Depression, ADHD and Other Neuropsychiatric Disorders". Heterocycles. 69 (1): 539. doi: 10.3987/REV-06-SR(O)1 . ISSN   0385-5414.
  6. ↑ Liu S, Molino BF (2007). "Chapter 2 Recent Developments in Monoamine Reuptake Inhibitors". Annual Reports in Medicinal Chemistry. Vol. 42. Elsevier. pp. 13–26. doi:10.1016/s0065-7743(07)42002-4. ISBN   978-0-12-373912-4.
  7. ↑ Stanford SC, Heal DJ (2019). "Catecholamines: Knowledge and understanding in the 1960s, now, and in the future". Brain Neurosci Adv. 3: 2398212818810682. doi:10.1177/2398212818810682. PMC   7058270 . PMID   32166174.
  8. 1 2 3 4 Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC   3666194 . PMID   23539642.
  9. 1 2 3 Rasmussen N (2015). "Amphetamine-Type Stimulants: The Early History of Their Medical and Non-Medical Uses". Int Rev Neurobiol. 120: 9–25. doi:10.1016/bs.irn.2015.02.001. PMID   26070751.
  10. ↑ Heal DJ, Cheetham SC, Smith SL (December 2009). "The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety". Neuropharmacology. 57 (7–8): 608–618. doi:10.1016/j.neuropharm.2009.08.020. PMID   19761781.
  11. ↑ Heal DJ, Smith SL (June 2022). "Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology". J Psychopharmacol. 36 (6): 680–703. doi:10.1177/02698811211032475. PMC   9150143 . PMID   34318734.
  12. ↑ Nishino S, Kotorii N (2016). "Overview of Management of Narcolepsy". Narcolepsy. Cham: Springer International Publishing. pp. 285–305. doi:10.1007/978-3-319-23739-8_21. ISBN   978-3-319-23738-1.
  13. ↑ Nishino S, Kotorii N (2016). "Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics". Narcolepsy. Cham: Springer International Publishing. pp. 307–329. doi:10.1007/978-3-319-23739-8_22. ISBN   978-3-319-23738-1.
  14. ↑ Aaron CK (August 1990). "Sympathomimetics". Emerg Med Clin North Am. 8 (3): 513–526. doi:10.1016/S0733-8627(20)30256-X. PMID   2201518.
  15. ↑ Hendeles L (1993). "Selecting a decongestant". Pharmacotherapy. 13 (6 Pt 2): 129S –134S, discussion 143S–146S. doi:10.1002/j.1875-9114.1993.tb02781.x. PMID   7507590.
  16. ↑ Barkholtz HM, Hadzima R, Miles A (July 2023). "Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature". ACS Pharmacol Transl Sci. 6 (7): 914–924. doi:10.1021/acsptsci.3c00019. PMC   10353062 . PMID   37470013.
  17. ↑ Wanka L, Iqbal K, Schreiner PR (May 2013). "The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives". Chem Rev. 113 (5): 3516–3604. doi:10.1021/cr100264t. PMC   3650105 . PMID   23432396.
  18. ↑ Sommerauer C, Rebernik P, Reither H, Nanoff C, Pifl C (March 2012). "The noradrenaline transporter as site of action for the anti-Parkinson drug amantadine". Neuropharmacology. 62 (4): 1708–1716. doi:10.1016/j.neuropharm.2011.11.017. PMID   22155208.
  19. ↑ Schmitt KC, Reith ME (February 2010). "Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse". Ann N Y Acad Sci. 1187: 316–340. doi:10.1111/j.1749-6632.2009.05148.x. PMID   20201860.
  20. ↑ Meyer MR (October 2016). "New psychoactive substances: an overview on recent publications on their toxicodynamics and toxicokinetics". Arch Toxicol. 90 (10): 2421–2444. Bibcode:2016ArTox..90.2421M. doi:10.1007/s00204-016-1812-x. PMID   27665567.
  21. 1 2 Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. OCLC   181862653. OL   18589888W.
  22. ↑ Gavai AK, Bouzembrak Y, van den Bulk LM, Liu N, van Overbeeke LF, van den Heuvel LJ, et al. (December 2021). "Artificial intelligence to detect unknown stimulants from scientific literature and media reports". Food Control. 130: 108360. doi: 10.1016/j.foodcont.2021.108360 . ISSN   0956-7135.
  23. 1 2 3 Costa VM, Grando LG, Milandri E, Nardi J, Teixeira P, Mladěnka P, et al. (November 2022). "Natural Sympathomimetic Drugs: From Pharmacology to Toxicology". Biomolecules. 12 (12): 1793. doi: 10.3390/biom12121793 . PMC   9775352 . PMID   36551221.
  24. 1 2 3 Rothman RB, Baumann MH (December 2005). "Targeted screening for biogenic amine transporters: potential applications for natural products". Life Sci. 78 (5): 512–518. doi:10.1016/j.lfs.2005.09.001. PMID   16202429.
  25. 1 2 3 4 Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, et al. (October 2003). "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". J Pharmacol Exp Ther. 307 (1): 138–145. doi:10.1124/jpet.103.053975. PMID   12954796.
  26. ↑ Gainetdinov RR, Hoener MC, Berry MD (July 2018). "Trace Amines and Their Receptors". Pharmacol Rev. 70 (3): 549–620. doi: 10.1124/pr.117.015305 . PMID   29941461.
  27. 1 2 3 4 Kohut SJ, Jacobs DS, Rothman RB, Partilla JS, Bergman J, Blough BE (December 2017). "Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys". Psychopharmacology (Berl). 234 (23–24): 3455–3465. doi:10.1007/s00213-017-4731-5. PMC   5747253 . PMID   28889212. 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.
  28. 1 2 Bauer CT (5 July 2014). Determinants of Abuse-Related Effects of Monoamine Releasers in Rats. VCU Scholars Compass (Thesis). doi:10.25772/AN08-SZ65 . Retrieved 24 November 2024. 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, [...]
  29. 1 2 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707.
  30. ↑ Ilipilla G, Arnold LE (23 May 2024). "The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium". Expert Opinion on Pharmacotherapy. 25 (8): 945–956. doi: 10.1080/14656566.2024.2369197 . ISSN   1465-6566. PMID   38900676.
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