Serotonin-dopamine reuptake inhibitor
A serotonin-dopamine reuptake inhibitor (SDRI) is a drug that acts as a reuptake inhibitor for 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.
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 extraordinarily difficult to tease apart affinity for the DAT from the norepinephrine transporter (NET) and inhibit the reuptake of dopamine alone. As a result, selective dopamine reuptake inhibitors (DRIs) are rare, and comparably, SDRIs are even more so. In fact, only two SDRIs are well-established in research at present, which are RTI-83 and UWA-101, though other related compounds are known. However, UWA-101 may 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 instead be an SDRA or serotonin-dopamine releasing agent (of which it would be the only one known to currently exist). 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.
For additional information on SRIs and DRIs, respectively, please refer to these articles:
- 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. doi:10.1208/aapsj0901001. PMC 2751297. PMID 17408232.
- 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. doi:10.1021/jm960409s. PMID 8831768.
- 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. doi:10.1096/fj.11-195016. PMID 22345403.
- Jin C, Navarro HA, Carroll FI. 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. 2008 Dec 25;51(24):8048-56. PMID 19053748
- Jin C, Navarro HA, Ivy Carroll F. 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. 2009 Jul 15;17(14):5126-32. PMID 19523837
- PMID 19038547