Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability.
Solis E
,
Partilla JS
,
Sakloth F
,
Ruchala I
,
Schwienteck KL
,
De Felice LJ
,
Eltit JM
,
Glennon RA
,
Negus SS
,
Baumann MH
.
???displayArticle.abstract???
Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds.
Bauer,
Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats.
2013, Pubmed
Bauer,
Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats.
2013,
Pubmed
Baumann,
Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products.
2013,
Pubmed
Baumann,
In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat.
2011,
Pubmed
Baumann,
Baths salts, spice, and related designer drugs: the science behind the headlines.
2014,
Pubmed
Baumann,
Psychoactive "bath salts": not so soothing.
2013,
Pubmed
Baumann,
Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.
2014,
Pubmed
,
Xenbase
Blanckaert,
4-Methyl-amphetamine: a health threat for recreational amphetamine users.
2013,
Pubmed
Blough,
Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics.
2014,
Pubmed
Bonano,
Abuse-related and abuse-limiting effects of methcathinone and the synthetic "bath salts" cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats.
2014,
Pubmed
Bonano,
Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues.
2015,
Pubmed
Cameron,
Amphetamine activates calcium channels through dopamine transporter-mediated depolarization.
2015,
Pubmed
Cameron,
Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter.
2013,
Pubmed
,
Xenbase
Czoty,
Serotonergic attenuation of the reinforcing and neurochemical effects of cocaine in squirrel monkeys.
2002,
Pubmed
De Felice,
Synthetic cathinones: chemical phylogeny, physiology, and neuropharmacology.
2014,
Pubmed
Fleckenstein,
New insights into the mechanism of action of amphetamines.
2007,
Pubmed
Hatcher-Solis,
G protein-coupled receptor signaling to Kir channels in Xenopus oocytes.
2014,
Pubmed
,
Xenbase
Hutsell,
Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats.
2016,
Pubmed
Kahlig,
Amphetamine induces dopamine efflux through a dopamine transporter channel.
2005,
Pubmed
Khoshbouei,
Amphetamine-induced dopamine efflux. A voltage-sensitive and intracellular Na+-dependent mechanism.
2003,
Pubmed
Koren,
Gating mechanism of a cloned potassium channel expressed in frog oocytes and mammalian cells.
1990,
Pubmed
,
Xenbase
Larsen,
The chicken serotonin transporter discriminates between serotonin-selective reuptake inhibitors. A species-scanning mutagenesis study.
2004,
Pubmed
Miller,
Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats.
2015,
Pubmed
Negus,
Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys.
2007,
Pubmed
Negus,
Intracranial self-stimulation to evaluate abuse potential of drugs.
2014,
Pubmed
Pörzgen,
The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines.
2001,
Pubmed
,
Xenbase
Rodriguez-Menchaca,
S(+)amphetamine induces a persistent leak in the human dopamine transporter: molecular stent hypothesis.
2012,
Pubmed
,
Xenbase
Rosenberg,
Effects of monoamine reuptake inhibitors in assays of acute pain-stimulated and pain-depressed behavior in rats.
2013,
Pubmed
Ross,
Substituted amphetamine derivatives. I. Effect on uptake and release of biogenic monoamines and on monoamine oxidase in the mouse brain.
1977,
Pubmed
Rothman,
Therapeutic potential of monoamine transporter substrates.
2006,
Pubmed
Rothman,
Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters.
2012,
Pubmed
Rothman,
(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters.
2003,
Pubmed
Rothman,
Dual dopamine/serotonin releasers: potential treatment agents for stimulant addiction.
2008,
Pubmed
Rubio,
Serotonin is involved in the psychostimulant and hypothermic effect of 4-methylamphetamine in rats.
2015,
Pubmed
Ruchala,
Electrical coupling between the human serotonin transporter and voltage-gated Ca(2+) channels.
2014,
Pubmed
Saha,
'Second-generation' mephedrone analogs, 4-MEC and 4-MePPP, differentially affect monoamine transporter function.
2015,
Pubmed
,
Xenbase
Sandtner,
Binding Mode Selection Determines the Action of Ecstasy Homologs at Monoamine Transporters.
2016,
Pubmed
Scholze,
Transporter-mediated release: a superfusion study on human embryonic kidney cells stably expressing the human serotonin transporter.
2000,
Pubmed
Simmler,
Monoamine transporter and receptor interaction profiles of a new series of designer cathinones.
2014,
Pubmed
Solis,
4-(4-(dimethylamino)phenyl)-1-methylpyridinium (APP+) is a fluorescent substrate for the human serotonin transporter.
2012,
Pubmed
,
Xenbase
Solis,
Electrophysiological Actions of Synthetic Cathinones on Monoamine Transporters.
2017,
Pubmed
,
Xenbase
Wang,
Estimating the relative reinforcing strength of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine.
2007,
Pubmed
Wee,
Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs.
2005,
Pubmed
