Pharmacologic Studies on the Structure-Activity Relationship of Hydroxyindole Alkylamines

Cerletti, A; Taeschler, M; Weidmann, Hans

doi:10.1016/s1054-3589(08)60322-1

Cited by 22 publications

(17 citation statements)

References 13 publications

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“…Interestingly, 5-IT, 6-(2-aminopropyl) indole (6-IT) and AMT (3-IT), for example, gave IC 50 values of 22, 4.6, and 58 μM, respectively. [7] In the present study, inhibition of MAO-A required a lower 5-IT concentration. [24] These data indicated that 6-IT was the most potent inhibitor amongst the three substances.…”

Section: Resultsmentioning

confidence: 48%

“…As a consequence, the Scientific Committee of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) carried out a risk assessment [1] in accordance with Article 6 of Council Decision 2005/387/JHA on information exchange, risk assessment, and control of new psychoactive substances. [7] Currently, there is a lack of detailed clinical and pre-clinical data on 5-IT. [3] 5-(2-Aminopropyl)indole appears to show relatively longlasting psychostimulant properties, [1,4] and although its preparation was first described in the 1960s, [5,6] few studies exist with regards to its biological effects.…”

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confidence: 99%

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5‐(2‐Aminopropyl)indole (5‐IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

Herraiz

Brandt

2013

Drug Testing and Analysis

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5-(2-Aminopropyl)indole (5-IT) is a psychoactive compound that has recently been associated with several fatal and non-fatal intoxications in a number of European countries. There are indications that acute effects may include symptoms of monoaminergic (e.g. serotonin) toxicity and one mechanism involved in the increase of serotonin levels includes the inhibition of monoamine oxidase. This study investigated the effect of 5-IT on human MAO-A and -B isozymes using kynuramine as the substrate. Substrate conversion to 4-hydroxyquinoline was monitored by high-performance liquid chromatography coupled to diode array detection. This method was employed to determine the extent of MAO inhibition (IC50 and Ki ) and it was found that 5-IT was a selective, competitive and reversible inhibitor of MAO-A. 5-IT revealed a relatively potent ability to inhibit MAO-A (IC50 =1.6 μM and Ki =0.25 μM) while MAO-B inhibition was not observed (0-500 μM 5-IT). Under identical experimental conditions, other established inhibitors of MAO-A and antidepressants provided the following IC50 values: clorgyline 16 nM, harmaline 20 nM, toloxatone 6.7 μM and moclobemide >500 μM. These data indicated that 5-IT was less potent than clorgyline and harmaline but more potent than toloxatone and moclobemide under the in-vitro conditions studied. The inhibition of MAO-A suggests that 5-IT by itself or in combination with other substances may be able to potentiate serotonergic/monoaminergic effects and further studies are needed to clarify its relevance to the adverse effects reported for 5-IT.

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Section: Resultsmentioning

confidence: 48%

mentioning

confidence: 99%

5‐(2‐Aminopropyl)indole (5‐IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

Herraiz

Brandt

2013

Drug Testing and Analysis

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“…Only very limited analog work has been reported in the psilocybin area, 5 and to our knowledge, no pharmacological testing of psilocybin or psilocin derivatives has been published since the discovery of 5-HT 2 receptor subtypes. 6,7 Although the amino acid sequence of the 5HT 2C receptor has been determined, little data are available regarding its three-dimensional structure 3 and therefore, our program has initially relied on an empirical approach.…”

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confidence: 99%

“…The compounds prepared (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) 8 are shown in Figure 2. Known N-methylated derivatives 3 and 4 were synthesized following published procedures.…”

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confidence: 99%

SAR of psilocybin analogs: Discovery of a selective 5-HT2C agonist

Sard

Kumaran

Morency

et al. 2005

Bioorganic & Medicinal Chemistry Letters

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“…Importantly, 5-IT and 6-IT contain the substructure of α-methylphenethylamine (i.e., amphetamine), suggesting the compounds may have stimulant or hallucinogenic properties (EMCDDA, 2014; Glennon, 2014; Rothman and Baumann, 2003). Older research shows that 6-IT is more potent than 5-IT with respect to antagonizing the pro-convulsant effects of reserpine, and inhibiting the activity of monoamine oxidase (Cerletti et al, 1968). More recent studies confirm that 5-IT acts as a selective, reversible and competitive inhibitor of monoamine oxidase A (MAO A) (Herraiz and Brandt, 2014), and 6-IT was shown to evoke release of DA, NE and 5-HT (Banks et al, 2014).…”

Section: 0 Introductionmentioning

confidence: 99%

The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue

et al. 2016

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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 releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at 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 the chemical structure of transporter ligands 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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Pharmacologic Studies on the Structure-Activity Relationship of Hydroxyindole Alkylamines

Cited by 22 publications

References 13 publications

5‐(2‐Aminopropyl)indole (5‐IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

5‐(2‐Aminopropyl)indole (5‐IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

SAR of psilocybin analogs: Discovery of a selective 5-HT2C agonist

The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue

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