Dopamine reuptake inhibitor
A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.
DRIs are used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy for their psychostimulant effects, and in the treatment of obesity and binge eating disorder for their appetite suppressant effects. They are sometimes used as antidepressants in the treatment of mood disorders, but their use as antidepressants is limited given that strong DRIs have a high abuse potential and legal restrictions on their use. Lack of dopamine reuptake and the increase in extracellular levels of dopamine have been linked to increased susceptibility to addictive behavior given increase in dopaminergic neurotransmission. The dopaminergic pathways are considered to be strong reward centers. Many DRIs such as cocaine are drugs of abuse due to the rewarding effects evoked by elevated synaptic concentrations of dopamine in the brain.
Society and culture
History of use
Until the 1950s, dopamine was thought to only contribute to the biosynthesis of norepinephrine and epinephrine. It was not until dopamine was found in the brain in similar levels as norepinephrine that the possibility was considered that its biological role might be other than the synthesis of the catecholamines.
The following drugs have DRI action and have been or are used clinically specifically for this property: amineptine, dexmethylphenidate, difemetorex, fencamfamine, lefetamine, levophacetoperane, medifoxamine, mesocarb, methylphenidate, nomifensine, pipradrol, prolintane, and pyrovalerone. The following drugs are or have been used clinically and possess only weak DRI action, which may or may not be clinically-relevant: adrafinil, armodafinil, bupropion, mazindol, modafinil, nefazodone, sertraline, and sibutramine. The following drugs are or have been clinically used but only coincidentally have DRI properties: benzatropine, diphenylpyraline, etybenzatropine, ketamine, nefopam, pethidine (meperidine), and tripelennamine. The following are a selection of some particularly notably abused DRIs: cocaine, ketamine, MDPV, naphyrone, and phencyclidine (PCP). Amphetamines, including amphetamine, methamphetamine, MDMA, cathinone, methcathinone, mephedrone, and methylone, are all DRIs as well, but are distinct in that they also behave, and potentially more potently as dopamine releasing agents (DRAs) (due to Yerkes–Dodson's law, 'more potently stimulated' may not equal more optimally functionally stimulated). There are very distinct differences in the mode of action between dopamine releasers/substrates & dopamine re-uptake inhibitors; the former are functionally entropy-driven (i.e. relating to hydrophobicity) and the latter are enthalpy-driven (i.e. relating conformational change). Reuptake inhibitors such as cocaine induce hyperpolarization of cloned human DAT upon oocytes that are naturally found on neurons, whereas releasing agents induce de-polarization of the neuron membrane.
The wakefulness-promoting agent modafinil and its analogues (e.g., adrafinil, armodafinil) have been approved to treat narcolepsy and shift work sleep disorder. These act as weak (micromolar) DRIs, but this effect does not correlate with wakefulness-promoting effects, suggesting the effect is too weak to be of clinical significance. The conclusion is these drugs promote wakefulness via some other mechanism.[disputed ]
DRIs have been explored as potential antiaddictive agents because of their ability to replace the reward effects received from other drugs. DRIs have been successfully used to serve as nicotine replacement in cases of smoking addiction and methadone replacement in the case of heroin addiction. DRIs have been explored as treatment for cocaine addiction, and have shown to alleviate cravings and self-administration.
Monoamine reuptake inhibitors, including DRIs, have also shown effectiveness as therapy for excessive food intake and appetite control for obese patients. Most drugs marketed for this purpose have been withdrawn or discontinued because of adverse side effects such as increase in blood pressure, as well as high abuse potential.
List of DRIs
Only DRIs which are selective for the DAT over the other monoamine transporters (MATs) are listed below. For a list of DRIs that act at multiple MATs, see other monoamine reuptake inhibitor pages such as NDRI and SNDRI.[disputed ]
Selective dopamine reuptake inhibitors
- 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
- Altropane (O-587)
- Amfonelic acid (WIN 25978)
- Amineptine (has a reasonable degree of selectivity for dopamine over norepinephrine reuptake inhibition)
- BTCP (GK-13)
- Difluoropine (O-620)
- Iometopane (β-CIT, RTI-55)
- Methylphenidate (has a mild degree of selectivity for dopamine over norepinephrine reuptake inhibition, although it significantly affects both)
- Ethylphenidate (more selective for DA vs NE reuptake inhibition compared to methylphenidate, but still has a marked effect on both)
- Modafinil (relatively weak but very selective for the dopamine transporter, with little to no effect on the norepinephrine or serotonin transporters)
- Armodafinil (R-enantiomer of modafinil; somewhat more potent at inhibiting DAT than racemic modafinil, with equally negligible action on NET and SERT)
- Vanoxerine (GBR-12909)
DRIs with substantial activity at other sites
- Adrafinil (weak, possibly stressful on liver)
- Benztropine (also muscarinic antagonist)
- Bupropion (also a weak NRI)
- Fluorenol (extremely weak)
- Medifoxamine (relatively weak)
- Metaphit (irreversible; depletes dopamine)
- Venlafaxine (weak)
- Chaenomeles speciosa (Flowering Quince)
- Oroxylin A (found in Oroxylum indicum and Scutellaria baicalensis (Skullcap))
- Song, R.; Zhang, H.-Y.; Li, X.; Bi, G.-H.; Gardner, E. L.; Xi, Z.-X. (2012). "Increased vulnerability to cocaine in mice lacking dopamine D3 receptors". Proceedings of the National Academy of Sciences. 109 (43): 17675–17680. doi:10.1073/pnas.1205297109. ISSN 0027-8424. PMC 3491487. PMID 23045656.
- Jack R. Cooper; Floyd E. Bloom; Robert H. Roth (1996). "9". The Biochemical Basis of Neuropharmacology (7th ed.). Oxford University Press, Inc. p. 293.
- Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al" Chem. Rev 2000, 100. 925-1024. ChemInform; May, 16th 2000, Volume 31, Issue 20, doi:[https://doi.org/10.1002%2Fchin.200020238 10.1002/chin.200020238. Page 928 (4th of article) 1st paragraph. Lines 8—11. Mirror hotlink.
- Bonnet JJ, Benmansour S, Costentin J, Parker EM, Cubeddu LX (1990). "Thermodynamic analyses of the binding of substrates and uptake inhibitors on the neuronal carrier of dopamine labeled with [3H]GBR 12783 or [3H]mazindol". J. Pharmacol. Exp. Ther. 253 (3): 1206–14. PMID 2141637.
- Cameron K, Kolanos R, Vekariya R, De Felice L, Glennon RA (2013). "Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of "bath salts," produce opposite effects at the human dopamine transporter". Psychopharmacology. 227 (3): 493–9. doi:10.1007/s00213-013-2967-2. PMC 3881434. PMID 23371489.
- Lacey MG, Mercuri NB, North RA (April 1990). "Actions of cocaine on rat dopaminergic neurones in vitro". Br. J. Pharmacol. 99 (4): 731–5. doi:10.1111/j.1476-5381.1990.tb12998.x. PMC 1917549. PMID 2361170.
- Kesselheim AS, Myers JA, Solomon DH, Winkelmayer WC, Levin R, Avorn J (2012). "The prevalence and cost of unapproved uses of top-selling orphan drugs". PLoS ONE. 7 (2): e31894. doi:10.1371/journal.pone.0031894. PMC 3283698. PMID 22363762.
- Loland, C.J.; M. Mereu; O.M. Okunola; J. Cao; T.E. Prisinzano; T. Kopajtic; L. Shi; J.L. Katz; G. Tanda; A.H. Newman (1 September 2012). "R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse". Biol. Psychiatry. 72 (5): 405–13. doi:10.1016/j.biopsych.2012.03.022. PMC 3413742. PMID 22537794.
- Wise RA (1996). "Neurobiology of addiction". Curr. Opin. Neurobiol. 6 (2): 243–51. doi:10.1016/S0959-4388(96)80079-1. PMID 8725967.
- Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". AAPS J. 8 (1): E196–203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128.
- Kintscher, U (2012). Reuptake Inhibitors of Dopamine, Noradrenaline, and Seratonin. Handbook of Experimental Pharmacology. 209. pp. 339–347. doi:10.1007/978-3-642-24716-3_15. ISBN 978-3-642-24715-6. PMID 22249822.
- Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". AAPS J. 8: E196–203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128.
- Zhao G, Jiang ZH, Zheng XW, Zang SY, Guo LH (September 2008). "Dopamine transporter inhibitory and antiparkinsonian effect of common flowering quince extract". Pharmacology Biochemistry and Behavior. 90 (3): 363–71. doi:10.1016/j.pbb.2008.03.014. PMID 18485464.
- Yoon, Seo Young; dela Peña, Ike; Kim, Sung Mok; Woo, Tae Sun; Shin, Chan Young; Son, Kun Ho; Park, Haeil; Lee, Yong Soo; Ryu, Jong Hoon; Jin, Mingli; Kim, Kyeong-Man; Cheong, Jae Hoon (2013). "Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro". Archives of Pharmacal Research. 36 (1): 134–140. doi:10.1007/s12272-013-0009-6. ISSN 0253-6269. PMID 23371806.