Monoamine neurotransmission is limited by perisynaptic transporters. Presynaptic monoamine transporters allow recycling of synaptically released noradrenaline, dopamine and 5-hydroxytryptamine.

[¹²⁵I]RTI55 labels all three monoamine transporters (NET, DAT and SERT) with affinities between 0.5 and 5 nM. Cocaine is an inhibitor of all three transporters with pK_i values between 6.5 and 7.2. Potential alternative splicing sites in non-coding regions of SERT and NET have been identified. A bacterial homologue of SERT shows allosteric modulation by selected anti-depressants [14].

1. Auerbach SS, DrugMatrix® and ToxFX® Coordinator National Toxicology Program. National Toxicology Program: Dept of Health and Human Services. Accessed on 02/05/2014. Modified on 02/05/2014. DrugMatrix, https://ntp.niehs.nih.gov/drugmatrix/index.html

2. Ben-Daniel R, Deuther-Conrad W, Scheunemann M, Steinbach J, Brust P, Mishani E. (2008) Carbon-11 labeled indolylpropylamine analog as a new potential PET agent for imaging of the serotonin transporter. Bioorg Med Chem, 16 (12): 6364-70. [PMID:18487050]

3. Froimowitz M, Gu Y, Dakin LA, Nagafuji PM, Kelley CJ, Parrish D, Deschamps JR, Janowsky A. (2007) Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem, 50 (2): 219-32. [PMID:17228864]

4. Gengo PJ, Giuliano F, McKenna KE et al.. (2005) Monoaminergic transporter binding and inhibition profile of dapoxetine, a medication for the treatment of premature ejaculation [abstract]. J Urol, 173: Abstract 878.

5. Gu H, Wall SC, Rudnick G. (1994) Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence. J Biol Chem, 269 (10): 7124-30. [PMID:8125921]

6. Gu HH, Wall S, Rudnick G. (1996) Ion coupling stoichiometry for the norepinephrine transporter in membrane vesicles from stably transfected cells. J Biol Chem, 271 (12): 6911-6. [PMID:8636118]

7. Lapinsky DJ, Velagaleti R, Yarravarapu N, Liu Y, Huang Y, Surratt CK, Lever JR, Foster JD, Acharya R, Vaughan RA et al.. (2011) Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling. Bioorg Med Chem, 19 (1): 504-12. [PMID:21129986]

8. Liu H, Altenbach RJ, Carr TL, Chandran P, Hsieh GC, Lewis LG, Manelli AM, Milicic I, Marsh KC, Miller TR et al.. (2008) cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia. J Med Chem, 51 (22): 7094-8. [PMID:18983139]

9. Mladenova G, Annedi SC, Ramnauth J, Maddaford SP, Rakhit S, Andrews JS, Zhang D, Porreca F. (2012) First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain. J Med Chem, 55 (7): 3488-501. [PMID:22420844]

10. Pristupa ZB, Wilson JM, Hoffman BJ, Kish SJ, Niznik HB. (1994) Pharmacological heterogeneity of the cloned and native human dopamine transporter: disassociation of [3H]WIN 35,428 and [3H]GBR 12,935 binding. Mol Pharmacol, 45 (1): 125-35. [PMID:8302271]

11. Raffel DM, Chen W. (2004) Binding of [3H]mazindol to cardiac norepinephrine transporters: kinetic and equilibrium studies. Naunyn Schmiedebergs Arch Pharmacol, 370 (1): 9-16. [PMID:15300361]

12. Reith ME, Xu C, Zhang L, Coffey LL. (1996) Translocation of dopamine and binding of WIN 35,428 measured under identical conditions in cells expressing the cloned human dopamine transporter. Naunyn Schmiedebergs Arch Pharmacol, 354 (3): 295-304. [PMID:8878059]

13. Rotella DP, McFarlane GR, Greenfield A, Grosanu C, Robichaud AJ, Denny RA, Feenstra RW, Núñez-García S, Reinders JH, Neut Mv et al.. (2009) Tetrahydrocarbazole-based serotonin reuptake inhibitor/dopamine D2 partial agonists for the potential treatment of schizophrenia. Bioorg Med Chem Lett, 19 (19): 5552-5. [PMID:19720528]

14. Singh SK, Yamashita A, Gouaux E. (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature, 448 (7156): 952-6. [PMID:17687333]

15. Talvenheimo J, Fishkes H, Nelson PJ, Rudnick G. (1983) The serotonin transporter-imipramine "receptor". J Biol Chem, 258 (10): 6115-9. [PMID:6853478]

16. Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol, 340 (2-3): 249-58. [PMID:9537821]

17. Wong EH, Sonders MS, Amara SG, Tinholt PM, Piercey MF, Hoffmann WP, Hyslop DK, Franklin S, Porsolt RD, Bonsignori A et al.. (2000) Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor. Biol Psychiatry, 47 (9): 818-29. [PMID:10812041]

18. Xu X, Wei Y, Guo Q, Zhao S, Liu Z, Xiao T, Liu Y, Qiu Y, Hou Y, Zhang G et al.. (2018) Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT_2A Antagonist Activity for the Treatment of Depression. J Pharmacol Exp Ther, 365 (3): 624-635. [PMID:29615471]

Stefan Bröer Research School of Biology Australian National University Linnaeus Way 134 Canberra, ACT, 0200 Australia Gary Rudnick (Past contributor) (Past contributor) Sterling Hall of Medicine, B-Wing 333 Cedar Street, Ste B334 New Haven, CT 06510