Selective NRAs include ephedrine, pseudoephedrine, phenylpropanolamine, levomethamphetamine, andD-phenylalaninol.[1][2][25][27] These drugs also release dopamine to a much lesser extent however (e.g., ~10- to 20-fold lesspotently).[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 (versusdextroamphetamine being roughly equipotent on norepinephrine and dopamine release in the same study).[21] NRAs play a significant role in treating ADHD, obesity, narcolepsy, and assympathomimetics by enhancing adrenergic signaling.[1][2][8][30]
^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.PMID19761781.
^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.ISBN978-3-319-23738-1.
^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.PMID22155208.
^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.PMID20201860.
^abcRothman 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.PMID16202429.
^abcdRothman 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.PMID12954796.
^abcdKohut 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.PMC5747253.PMID28889212.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.
^abBauer CT (5 July 2014).Determinants of Abuse-Related Effects of Monoamine Releasers in Rats.VCU Scholars Compass (Thesis).doi:10.25772/AN08-SZ65. Retrieved24 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, [...]
^abRothman 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.PMID11071707.
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