Application of a Combined Approach to Identify New Psychoactive Street Drugs and Decipher Their Mechanisms at Monoamine Transporters

Overview

Journal Curr Top Behav Neurosci

Publisher Springer

Specialty Psychology

Date 2016 Dec 28

PMID 28025810

Citations 19

Authors

Felix P Mayer

Anton Luf

Constanze Nagy

Marion Holy

Rainer Schmid

Michael Freissmuth

Harald H Sitte

Affiliations

Soon will be listed here.

Abstract

Psychoactive compounds can cause acute and long-term health problems and lead to addiction. In addition to well-studied and legally controlled compounds like cocaine, new psychoactive substances (NPS) are appearing in street drug markets as replacement strategies and legal alternatives. NPS are effectively marketed as "designer drugs" or "research chemicals" without any knowledge of their underlying pharmacological mode of action and their potential toxicological effects and obviously devoid of any registration process. As of 2016, the knowledge of structure-activity relationships for most NPS is scarce, and predicting detailed pharmacological activity of newly emerging drugs is a challenging task. Therefore, it is important to combine different approaches and employ biological test systems that are superior to mere chemical analysis in recognizing novel and potentially harmful street drugs. In this chapter, we provide a detailed description of techniques to decipher the molecular mechanism of action of NPS that target the high-affinity transporters for dopamine, norepinephrine, and serotonin. In addition, this chapter provides insights into a combined approach to identify and characterize new psychoactive street drugs of unknown content in a collaboration with the Austrian prevention project "checkit!."

Citing Articles

Bioisosteric analogs of MDMA: Improving the pharmacological profile?.

Alberto-Silva A, Hemmer S, Bock H, da Silva L, Scott K, Kastner N J Neurochem. 2024; 168(9):2022-2042.

PMID: 38898705 PMC: 11449655. DOI: 10.1111/jnc.16149.

5-HT_FAsTR: a versatile, label-free, high-throughput, fluorescence-based microplate assay to quantify serotonin transport and release.

Bukowski L, Strom M, Andersen J, Maesen J, Tian L, Sinning S Sci Rep. 2024; 14(1):6541.

PMID: 38504103 PMC: 10951269. DOI: 10.1038/s41598-024-56712-z.

Exploring the topic structure and abuse trends of new psychoactive Substance since the 21st century from a bibliometric perspective.

Hou X, Wang J, Zhang Y, Zhang Y, Shangguan J, Qin G Saudi Pharm J. 2024; 32(4):101991.

PMID: 38414783 PMC: 10897889. DOI: 10.1016/j.jsps.2024.101991.

Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors.

Gradisch R, Schlogl K, Lazzarin E, Niello M, Maier J, Mayer F Nat Commun. 2024; 15(1):417.

PMID: 38195746 PMC: 10776687. DOI: 10.1038/s41467-023-44637-6.

Development and validation of an automated microfluidic perfusion platform for parallelized screening of compounds in vitro.

Brugnoli F, Holy M, Niello M, Maier J, Hanreich M, Menzel M Basic Clin Pharmacol Toxicol. 2023; 133(5):535-547.

PMID: 37658634 PMC: 10952622. DOI: 10.1111/bcpt.13940.

References

Baumeister D, Tojo L, Tracy D . Legal highs: staying on top of the flood of novel psychoactive substances. Ther Adv Psychopharmacol. 2015; 5(2):97-132. PMC: 4521440. DOI: 10.1177/2045125314559539. View

Lewin A, Seltzman H, Carroll F, Mascarella S, Anantha Reddy P . Emergence and properties of spice and bath salts: a medicinal chemistry perspective. Life Sci. 2013; 97(1):9-19. DOI: 10.1016/j.lfs.2013.09.026. View

Brandt S, King L, Evans-Brown M . The new drug phenomenon. Drug Test Anal. 2014; 6(7-8):587-97. DOI: 10.1002/dta.1686. View

Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wiggermann M, Ernst L . Spice: a never ending story?. Forensic Sci Int. 2009; 191(1-3):58-63. DOI: 10.1016/j.forsciint.2009.06.008. View

Baumann M, Solis Jr E, Watterson L, Marusich J, Fantegrossi W, Wiley J . Baths salts, spice, and related designer drugs: the science behind the headlines. J Neurosci. 2014; 34(46):15150-8. PMC: 4228124. DOI: 10.1523/JNEUROSCI.3223-14.2014. View

Miliano C, Serpelloni G, Rimondo C, Mereu M, Marti M, De Luca M . Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants. Front Neurosci. 2016; 10:153. PMC: 4835722. DOI: 10.3389/fnins.2016.00153. View

Prosser J, Nelson L . The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2011; 8(1):33-42. PMC: 3550219. DOI: 10.1007/s13181-011-0193-z. View

Ross E, Watson M, Goldberger B . "Bath salts" intoxication. N Engl J Med. 2011; 365(10):967-8. DOI: 10.1056/NEJMc1107097. View

Soussan C, Kjellgren A . The users of Novel Psychoactive Substances: Online survey about their characteristics, attitudes and motivations. Int J Drug Policy. 2016; 32:77-84. DOI: 10.1016/j.drugpo.2016.03.007. View

10.

Torres G, Gainetdinov R, Caron M . Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci. 2003; 4(1):13-25. DOI: 10.1038/nrn1008. View

11.

Sitte H, Freissmuth M . The reverse operation of Na(+)/Cl(-)-coupled neurotransmitter transporters--why amphetamines take two to tango. J Neurochem. 2009; 112(2):340-55. PMC: 4497806. DOI: 10.1111/j.1471-4159.2009.06474.x. View

12.

Sitte H, Freissmuth M . Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci. 2014; 36(1):41-50. PMC: 4502921. DOI: 10.1016/j.tips.2014.11.006. View

13.

Sulzer D, Sonders M, Poulsen N, Galli A . Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol. 2005; 75(6):406-33. DOI: 10.1016/j.pneurobio.2005.04.003. View

14.

Egana L, Cuevas R, Baust T, Parra L, Leak R, Hochendoner S . Physical and functional interaction between the dopamine transporter and the synaptic vesicle protein synaptogyrin-3. J Neurosci. 2009; 29(14):4592-604. PMC: 2846176. DOI: 10.1523/JNEUROSCI.4559-08.2009. View

15.

Schuldiner S, Yelin R, Wall S, Rudnick G . Amphetamine derivatives interact with both plasma membrane and secretory vesicle biogenic amine transporters. Mol Pharmacol. 1993; 44(6):1227-31. View

16.

Freyberg Z, Sonders M, Aguilar J, Hiranita T, Karam C, Flores J . Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun. 2016; 7:10652. PMC: 4757768. DOI: 10.1038/ncomms10652. View

17.

Baumann M, Bulling S, Benaderet T, Saha K, Ayestas M, Partilla J . Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates. Neuropsychopharmacology. 2013; 39(6):1355-65. PMC: 3988539. DOI: 10.1038/npp.2013.331. View

18.

Pifl C, Reither H, Hornykiewicz O . The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter. Eur J Pharmacol. 2015; 755:119-26. DOI: 10.1016/j.ejphar.2015.03.004. View

19.

Stockner T, Montgomery T, Kudlacek O, Weissensteiner R, Ecker G, Freissmuth M . Mutational analysis of the high-affinity zinc binding site validates a refined human dopamine transporter homology model. PLoS Comput Biol. 2013; 9(2):e1002909. PMC: 3578762. DOI: 10.1371/journal.pcbi.1002909. View

20.

Penmatsa A, Gouaux E . How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters. J Physiol. 2013; 592(5):863-9. PMC: 3948551. DOI: 10.1113/jphysiol.2013.259051. View