Serotonin-dopamine reuptake inhibitor

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Chemical structure of the monoamine and indole neurotransmitter serotonin.
Chemical structure of the monoamine and catecholamine neurotransmitter dopamine.

A serotonin-dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

A closely related type of drug is a serotonin-dopamine releasing agent (SDRA).

Comparison to SNDRIs[edit]

Relative to serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), which also inhibit the reuptake of norepinephrine in addition to serotonin and dopamine, SDRIs might be expected to have a reduced incidence of certain side effects, namely insomnia, appetite loss, anxiety, and heart rate and blood pressure changes.[1]

Examples of SDRIs[edit]

Unlike the case of other combination monoamine reuptake inhibitors such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and norepinephrine-dopamine reuptake inhibitors (NDRIs), on account of the very similar chemical structures of their substrates, it is exceptionally difficult to tease apart affinity for the DAT from the norepinephrine transporter (NET) and inhibit the reuptake of dopamine alone.[2] As a result, selective dopamine reuptake inhibitors (DRIs) are rare, and comparably, SDRIs are even more so.

Pharmaceutical drugs[edit]

Medifoxamine (Cledial, Gerdaxyl) is an antidepressant that appears to act as an SDRI as well as a 5-HT2 receptor antagonist.[3] Sibutramine (Reductil, Meridia, Siredia, Sibutrex) is a withdrawn anorectic that itself as a molecule in vitro is an SNDRI but preferentially an SDRI, with 18.3- and 5.8-fold preference for inhibiting the reuptake of serotonin and dopamine over norepinephrine, respectively.[4] However, the metabolites of sibutramine are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and sibutramine appears to be acting in vivo mainly as a prodrug to them; accordingly, it was found to act as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak inhibition of dopamine reuptake (16%).[5][6][7]

Research chemicals[edit]

Compound 16b. The opposite enantiomer is ent-16b. (Manning 2009)

Two SDRIs that are known in research at present are RTI-83 and UWA-101,[8][9] though other related compounds are also known.[10][11] Based on its chemical structure, UWA-101 may actually also possess some activity as a releasing agent, and if so, unlike RTI-83, it would not be an SDRI in the purest sense and would also be an SDRA.[9] Manning et al. presented two high-affinity MAT-ligands with good binding selectivity for SERT and DAT, namely the 4-indolyl and 1-naphthyl arylalkylamines ent-16b (Ki 0.82, 3.8, 4840 nM for SERT, DAT, NET) and ent-13b respectively.[12]

See also[edit]


  1. ^ Banks, Matthew L.; Bauer, Clayton T.; Blough, Bruce E.; Rothman, Richard B.; Partilla, John S.; Baumann, Michael H.; Negus, S. Stevens (2014). "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys.". Experimental and Clinical Psychopharmacology. 22 (3): 274–284. ISSN 1936-2293. PMC 4067459Freely accessible. PMID 24796848. doi:10.1037/a0036595. 
  2. ^ Rothman RB, Blough BE, Baumann MH (2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal. 9 (1): E1–10. PMC 2751297Freely accessible. PMID 17408232. doi:10.1208/aapsj0901001. 
  3. ^ Gainsborough N, Nelson ML, Maskrey V, Swift CG, Jackson SH (1994). "The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers". Eur. J. Clin. Pharmacol. 46 (2): 163–6. PMID 8039537. doi:10.1007/bf00199882. 
  4. ^ Oh, Sangmi; Kim, Koon; Chung, Young; Shong, Minho; Park, Seung (2009). "Anti-obesity Agents: A Focused Review on the Structural Classification of Therapeutic Entities". Current Topics in Medicinal Chemistry. 9 (6): 466–481. ISSN 1568-0266. doi:10.2174/156802609788897862. 
  5. ^ Kim, K A; Song, W K; Park, J Y (2009). "Association of CYP2B6, CYP3A5, and CYP2C19 Genetic Polymorphisms With Sibutramine Pharmacokinetics in Healthy Korean Subjects". Clinical Pharmacology & Therapeutics. 86 (5): 511–518. ISSN 0009-9236. doi:10.1038/clpt.2009.145. 
  6. ^ Hofbauer, Karl (2004). Pharmacotherapy of obesity : options and alternatives. Boca Raton, Fla: CRC Press. ISBN 0-415-30321-4. 
  7. ^ "Meridia (sibutramine hydrochloride monohydrate) Label" (PDF). Abbott Laboratories, North Chicago, IL 60064, U.S.A. Retrieved 6 February 2016. 
  8. ^ Blough BE, Abraham P, Lewin AH, Kuhar MJ, Boja JW, Carroll FI (September 1996). "Synthesis and transporter binding properties of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters: serotonin transporter selective analogs". Journal of Medicinal Chemistry. 39 (20): 4027–35. PMID 8831768. doi:10.1021/jm960409s. 
  9. ^ a b Johnston TH, Millar Z, Huot P, et al. (February 2012). "A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances l-DOPA benefit in parkinsonian primates". FASEB J. 26 (5): 2154–63. PMID 22345403. doi:10.1096/fj.11-195016. 
  10. ^ Jin C, Navarro HA, Carroll FI (Dec 2008). "Development of 3-phenyltropane analogues with high affinity for the dopamine and serotonin transporters and low affinity for the norepinephrine transporter". Journal of Medicinal Chemistry. 51 (24): 8048–56. PMC 2841478Freely accessible. PMID 19053748. doi:10.1021/jm801162z. 
  11. ^ Jin C, Navarro HA, Ivy Carroll F (Jul 2009). "Synthesis and structure-activity relationship of 3beta-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3beta-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters". Bioorganic and Medicinal Chemistry. 17 (14): 5126–32. PMC 2747657Freely accessible. PMID 19523837. doi:10.1016/j.bmc.2009.05.052. 
  12. ^ Manning JR, Sexton T, Childers SR, Davies HM (January 2009). "1-Naphthyl and 4-indolyl arylalkylamines as selective monoamine reuptake inhibitors". Bioorg. Med. Chem. Lett. 19 (1): 58–61. PMID 19038547. doi:10.1016/j.bmcl.2008.11.022.