- Substantial progress was made on this project, with six original research articles and one lay-friendly review published. Along with our collaborators, we have characterized the pharmacological effects of numerous synthetic cannabinoids and synthetic cathinones found in the street drug marketplace. In particular, we described the pharmacology of 5-IT and 6-IT, two new designer drugs associated with several deaths in Europe. Our data demonstrate that these drugs are powerful monoamine releasing agent similar to 3,4-methylenedioxmethamphetamine but more potent. In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective effects of MDMA, 5-IT was selective for DAT over SERT, while 6-IT was selective for SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in chemical structure can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.

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Baumann, Michael H; Majumdar, Susruta; Le Rouzic, Valerie et al. (2018) Pharmacological characterization of novel synthetic opioids (NSO) found in the recreational drug marketplace. Neuropharmacology 134:101-107
Prekupec, Matthew P; Mansky, Peter A; Baumann, Michael H (2017) Misuse of Novel Synthetic Opioids: A Deadly New Trend. J Addict Med 11:256-265
Solis Jr, Ernesto; Partilla, John S; Sakloth, Farhana et al. (2017) N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability. Neuropsychopharmacology 42:1950-1961
Elmore, Joshua S; Dillon-Carter, Ora; Partilla, John S et al. (2017) Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats. Neuropsychopharmacology 42:649-660
Hoffman, Alexander F; Lycas, Matthew D; Kaczmarzyk, Jakub R et al. (2017) Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with ?9 -tetrahydrocannabinol. Addict Biol 22:390-399
Baumann, Michael H; Bukhari, Mohammad O; Lehner, Kurt R et al. (2017) Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs. Curr Top Behav Neurosci 32:93-117
McLaughlin, Gavin; Morris, Noreen; Kavanagh, Pierce V et al. (2017) Synthesis, characterization and monoamine transporter activity of the new psychoactive substance mexedrone and its N-methoxy positional isomer, N-methoxymephedrone. Drug Test Anal 9:358-368
Shekar, Aparna; Aguilar, Jenny I; Galli, Greta et al. (2017) Atypical dopamine efflux caused by 3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter. J Chem Neuroanat 83-84:69-74
Baumann, Michael H (2016) The Changing Face of Recreational Drug Use. Cerebrum 2016:
Hutsell, Blake A; Baumann, Michael H; Partilla, John S et al. (2016) Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats. Eur Neuropsychopharmacol 26:288-297

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