Dopamine reuptake inhibitor

A dopamine reuptake inhibitor (DRI) is a type 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, in turn, leads to increased extracellular concentrations of dopamine and therefore an increase in dopaminergic neurotransmission.[1]

DRIs are frequently used in the treatment of conditions like ADHD and narcolepsy on account of their psychostimulant effects and in the treatment of obesity due to their appetite suppressant properties. They have also been used as antidepressants in the treatment of mood disorders, but their use for this indication has been limited on account of their abuse potential and legal restrictions. Lack of dopamine reuptake and the increase in extracellular levels of dopamine have been linked to increased susceptibility to addictive behavior due to the increase in dopaminergic neurotransmission. The dopaminergic pathways are considered to be strong reward centers. In addition, 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 be nothing but part of the biosynthesis of norepinephrine and epinephrine. It was not until dopamine was found in the brain in same levels as norepinephrine that it was considered that dopamine might have a biological role other than the synthesis of the catecholamines.[2]

Pharmacotherapeutic uses

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. And, while virtually all DRIs are abused recreationally, the following are a selection of some particularly notable ones: 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 additionally behave, and often much more potently, as dopamine releasing agents (DRAs) (it should be noted that due to Yerkes–Dodson's law, 'more potently stimulated' may not equal more optimally functionally stimulated). However it should be taken into account that there remain very distinct differences in the mode of action between dopamine releasers/substrates & dopamine re-uptake inhibitors; in that the former are functionally entropy-driven (i.e. relating to hydrophobicity) and the latter are enthalpy-driven (i.e. relating conformational change).[3][4] Also contrasting the two, reuptake inhibitors such as cocaine induce hyperpolarization of cloned human DAT upon oocytes that are naturally found on neurons, whereas releasing agents like amphetamine induce de-polarization of the neuron membrane.[5][6]

Recently, the FDA-approved wakefulness-promoting agent modafinil and its analogues (e.g., adrafinil, armodafinil, fluorenol), which are approved to treat narcolepsy and shift work sleep disorder,[7] were found to act as weak (micromolar) DRIs.[8] However, this property has been found to not correlate with their wakefulness-promoting effects, suggesting that it is too weak to be of clinical significance and that these drugs promote wakefulness via some other mechanism.[9]

DRIs have been explored as potential antiaddictive agents because of their ability to replace reward received from other drugs. DRIs have been successfully used to serve as nicotine replacements in cases of smoking addictions well as methadone replacements in the case of heroin addiction. DRIs have been explored as potential substitutes for cocaine addiction, and have been shown to alleviate cravings and self-administration.[10]

Monoamine reuptake inhibitors, including DRIs, have also been shown to be effective as therapy for food intake and appetite control for obese subjects. However, most marketed drugs for this purpose have been withdrawn or discontinued due to adverse side effects such as increase in blood pressure and high abuse potential.[11]

List of DRIs

3D structure of RTI-470, a high-affinity and selective DAT ligand[12]

Many DRIs exist, an assortment which are listed below. Note that 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.

Selective dopamine reuptake inhibitors

DRIs with activity at other sites

Other DRIs

See also

References

  1. ↑ 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.
  2. ↑ Jack R. Cooper; Floyd E. Bloom; Robert H. Roth (1996). "9". The Biochemical Basis of Neuropharmacology (7th ed.). Oxford University Press, Inc. p. 293.
  3. ↑ Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000 ISSN 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, doi:10.1002/chin.200020238. Page 928 (4th of article) 1st paragraph. Lines 8—11. Mirror hotlink.
  4. ↑ Bonnet, J.-J.; Benmansour, S.; Costenin, J.; Parker, E. M.; Cubeddu, L. X. J. Pharmacol. Exp. Ther. 1990, 253, 1206.
  5. ↑ Mephedrone and Methylenedioxypyrovalerone (MDPV), Major Constituents of Bath Salts, Produce Opposite Effects at the Human Dopamine Transporter doi: 10.1007/s00213-013-2967-2.PMCID: PMC3881434. NIHMSID: NIHMS441214. Psychopharmacology (Berl). 2013 June; 227(3): 10.1007/s00213-013-2967-2.
  6. ↑ Actions of cocaine on rat dopaminergic neurones in vitro. Br J Pharmacol. 1990 Apr;99(4):731-5. PMID 2361170. PMCID: PMC1917549
  7. ↑ Kesselheim AS, Myers JA, Solomon DH, Winkelmayer WC, Levin R, Avorn J (February 21, 2012). Alessi-Severini, Silvia, ed. "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.
  8. ↑ 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.
  9. ↑ Wise RA (1996). "Neurobiology of addiction". Curr. Opin. Neurobiol. 6 (2): 243–51. doi:10.1016/S0959-4388(96)80079-1. PMID 8725967.
  10. ↑ 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.
  11. ↑ Kintscher, U (2012). "Reuptake Inhibitors of Dopamine, Noradrenaline, and Seratonin". Handbook of Experimental Pharmocology 209: 339–347. doi:10.1007/978-3-642-24716-3_15.
  12. ↑ doi:10.1208/aapsj080124 PMID 16584128
  13. ↑ 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.
  14. ↑ 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.

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