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Kalam M.A.,Sul Ross State University | Klein M.T.,Sul Ross State University | Hulsey D.,Sul Ross State University | Trout K.,Cactus Conservation Institute | And 2 more authors.
Journal of the Botanical Research Institute of Texas | Year: 2013

A phytochemical analytical study was conducted to address the question of whether the mescaline concentration in Lophophora williomsii (peyote) is dependent on the maturity and/or size of the plant. Samples of crown tissue (4 g each) biopsied from mature peyote cacti and whole small regrowth crowns (2-4 g each) were collected from the same population in the Tamaulipan Thomscrub ecoregion of South Texas. For each of the two groups (mature and small regrowth), the individual tissue samples were pooled, desiccated, and ground to powder. The alkaloids were extracted with methanol at 25°C, followed by evaporation of the methanol to dryness, then acid-base cleanup with water and dichloromethane. The mescaline concentration in each of the extracts was then determined by HPLC. Quantitative analyses provided evidence that the small crowns that develop in response to harvesting contain a lower mescaline concentration-about half as much-compared to that of crowns of mature unharvested plants in the same population. The deficiency in the mescaline concentration of these regrowth buttons (new crowns) exacerbates the problem posed by the small size of the buttons; that is, it further increases the number of buttons that must be consumed to obtain an efficacious dose for ceremonial use by members of the Native American Church (NAC). That means that either the NAC members must consume less than the traditional amount of peyote, or there will be increased demand for peyote. Any increase in demand, reflected in the price, will engender more intensive harvesting, which will inevitably have adverse effects on both the supply of sacrament for the NAC and the conservation status of L. williamsii wherever the harvesters have access to peyote populations.

Baumann M.H.,U.S. National Institute on Drug Abuse | Ayestas Jr. M.A.,U.S. National Institute on Drug Abuse | Partilla J.S.,U.S. National Institute on Drug Abuse | Sink J.R.,U.S. National Institute on Drug Abuse | And 6 more authors.
Neuropsychopharmacology | Year: 2012

The nonmedical use of designer cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Brandt S.D.,Liverpool John Moores University | Tearavarich R.,Khon Kaen University | Dempster N.,Liverpool John Moores University | Cozzi N.V.,University of Wisconsin - Madison | Daley P.F.,Alexander Shulgin Research Institute
Drug Testing and Analysis | Year: 2012

The absence of reference material is a commonly experienced difficulty among medical and forensic professionals tasked with identifying new psychoactive substances that are encountered for the first time. The identification of newly emerging substances lies at the heart of forensic and clinical analysis, and a proactive public health policy calls for a thorough analysis of the properties of new psychoactive substances before they appear in the emergency clinic, where they may be noticed because of adverse reactions or toxicity. For example, a wide range of N,N-dialkyltryptamines show psychoactive properties in humans and these tryptamines are sometimes encountered as intoxicants. However, most of the existing reference data on new psychoactive tryptamines have been obtained retrospectively, after reports of acute toxicities. To address the need for reference standards for new tryptamines, thirteen 5-methoxy-2-methyl-N,N-dialkyltryptamines were prepared. Analytical characterization was based on 1H and 13C nuclear magnetic resonance (NMR), gas chromatography-electron ionization ion-trap mass spectrometry (GC-EI-IT-MS) and chemical ionization-ion-trap tandem mass spectrometry (CI-IT-MS/MS), respectively. Differentiation among isomers was feasible by NMR and MS. In addition to the expected iminium ion base peak, indole-related key ions were detected under EI-IT-MS conditions at m/z 174, 159, 131, 130, and 103. CI-IT-MS/MS analysis of the 5-methoxy-2-methyl derivatives revealed the presence of m/z 188 in addition to [M+H] + and the iminium species. This study served as an extension from previous work on isomeric 5-ethoxylated counterparts and confirmed the ability to differentiate between the two groups. The data provided here add to the existing body of literature and aim to serve both forensic and clinical communities. © 2012 John Wiley & Sons, Ltd.

Brandt S.D.,Liverpool John Moores University | Daley P.F.,Alexander Shulgin Research Institute | Cozzi N.V.,University of Wisconsin - Madison
Drug Testing and Analysis | Year: 2012

Cathinone derivatives display a wide range of pharmacological activities and uses; some of them are used as prescription medicines, while others are encountered within a recreational context and are available without a prescription over the Internet and in retail shops around the world. One of the difficulties involved in the unambiguous identification of these new psychoactive substances is the lack of suitable reference standards, particularly when dealing with unreported derivatives and positional isomers. In order to address this need, three trifluoromethyl analogues of the psychostimulant methcathinone, with a CF 3 substituent at the 2-, 3- and 4-position of the phenyl ring (2-TFMAP1, 3-TFMAP2 and 4-TFMAP3), have been prepared for analytical characterization using ATR-FTIR, 1H and 13C NMR, and GC-(EI/CI)-ion trap-MS. Differentiation among isomers was feasible by IR, for example when assessing the carbonyl stretch at 1711 (1), 1693 (2) and 1688 (3) cm -1, respectively. In addition to the expected iminium base peak at m/z 58, EI-MS displayed key ions at m/z 173, 145, 125, 95, and 75. Separation of isomers was possible under GC conditions. A characteristic feature under CI conditions was the loss of water from the [M+H] + yielding m/z 214 in addition to m/z 58. Studies currently underway show that the three CF 3-methcathinone analogues have central nervous system effects and that the 4-CF 3 isomer 3 is more potent as a serotonin uptake inhibitor and releasing agent than the 3-CF 3 and 2-CF 3 counterparts. © 2012 John Wiley & Sons, Ltd.

Cozzi N.V.,Alexander Shulgin Research Institute | Cozzi N.V.,University of Wisconsin - Madison | Daley P.F.,Alexander Shulgin Research Institute
Bioorganic and Medicinal Chemistry Letters | Year: 2016

N,N-Diallyltryptamine (DALT) and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander Shulgin. In self-experiments, 5-MeO-DALT was reported to be psychoactive in the 12-20 mg range, while the unsubstituted compound DALT had few discernible effects in the 42-80 mg range. Recently, 5-MeO-DALT has been used in nonmedical settings for its psychoactive effects, but these effects have been poorly characterized and little is known of its pharmacological properties. We extended the work of Shulgin by synthesizing additional 5-substituted-DALTs. We then compared them to DALT and 5-MeO-DALT for their binding affinities at 45 cloned receptors and transporter proteins. Based on in vitro binding affinity, we identified 27 potential receptor targets for the 5-substituted-DALT compounds. Five of the DALT compounds had affinity in the 10-80 nM range for serotonin 5-HT1Aand 5-HT2Breceptors, while the affinity of DALT itself at 5-HT1Areceptors was slightly lower at 100 nM. Among the 5-HT2subtypes, the weakest affinity was at 5-HT2Areceptors, spanning 250-730 nM. Five of the DALT compounds had affinity in the 50-400 nM range for serotonin 5-HT1D, 5-HT6, and 5-HT7receptors; again, it was the unsubstituted DALT that had the weakest affinity at all three subtypes. The test drugs had even weaker affinity for 5-HT1B, 5-HT1E, and 5-HT5Asubtypes and little or no affinity for the 5-HT3subtype. These compounds also had generally nanomolar affinities for adrenergic α2A, α2B, and α2Creceptors, sigma receptors σ1and σ2, histamine H1receptors, and norepinephrine and serotonin uptake transporters. They also bound to other targets in the nanomolar-to-low micromolar range. Based on these binding results, it is likely that multiple serotonin receptors, as well as several nonserotonergic sites are important for the psychoactive effects of DALT drugs. To learn whether any quantitative structure-affinity relationships existed, we evaluated correlations among physicochemical properties of the congeneric 5-substituted-DALT compounds. The descriptors included electronic (σp), hydrophobic (π), and steric (CMR) parameters. The binding affinity at 5-HT1A, 5-HT1D, 5-HT7, and κ opioid receptors was positively correlated with the steric volume parameter CMR. At α2A, α2B, and α2Creceptors, and at the histamine H1receptor, binding affinity was correlated with the Hammett substituent parameter σp; higher affinity was associated with larger σpvalues. At the σ2receptor, higher affinity was correlated with increasing π. These correlations should aid in the development of more potent and selective drugs within this family of compounds. © 2015 Elsevier Ltd. All rights reserved.

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