5-Chloro-αET

5-Chloro-αET (code name PAL-526), or 5-chloro-AET, also known as 5-chloro-α-ethyltryptamine, is a serotonergic agent of the tryptamine and α-alkyltryptamine families.^[1] It is the derivative of α-ethyltryptamine (αET or AET) with a 5-chloro substitution.^[1] Analogues of 5-chloro-αET include 5-fluoro-αET, 5-chloro-αMT, and 5-fluoro-αMT.^[1]

The drug is known to act as a potent serotonin releasing agent (SRA) and relatively weak serotonin 5-HT_2A receptor near-full agonist.^[1] It shows negligible induction of norepinephrine and dopamine release but does act as a very weak dopamine reuptake inhibitor (DRI).^[1] 5-Chloro-αET's EC₅₀ and IC₅₀ values are 33.2 nM for serotonin release, 249 nM (E_max = 87%) for serotonin 5-HT_2A receptor agonism (7.5-fold lower than for serotonin release), 1,838 nM for dopamine reuptake inhibition (55-fold lower than for serotonin release), and >10,000 nM for norepinephrine release.^[1] The monoamine release assays were performed in rat brain synaptosomes.^[1]

Several close analogues of 5-chloro-αET, including 5-chloro-αMT and 5-fluoro-αMT, are known to be potent monoamine oxidase inhibitors (MAOIs), specifically of monoamine oxidase A (MAO-A).^[2]

5-Chloro-AET was first described in the scientific literature by at least 1963.^[3]^[4]

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 ^1.5 ^1.6 "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorg Med Chem Lett 24 (19): 4754–4758. October 2014. doi:10.1016/j.bmcl.2014.07.062. PMID 25193229. "The racemic a-alkyl tryptamines 7a, 7b, 7c, 7d, 7e, and 7f were synthesized by nitro olefin formation followed by lithium ammonium hydride reduction (Scheme 2).32 [...] a-Ethylation of the 5-chloro and 5-fluoro substituted tryptamines, to form 7e and 7f respectively, also weakened NE release activity compared to their a-methyl analogs, but 7e flipped to become a weak DA uptake inhibitor. [...] In the a-ethyltryptamine series, the 5-chloro analog (7e) and 5-fluoro analog (7f) both weakened substantially as 5-HT2A agonists compared to their a-methyl- and non-alkylated tryptamine analogs (7b/7c and 4h/4j), with EC50 values of 249 nM and 246 nM, respectively. [...] Table 1 Comparison of the DAT, SERT, and NET-mediated release activity and 5-HT2A receptor activity of substituted tryptamines [...] ^d Value is IC50 for uptake inhibition in nM.".
↑ "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol 10. 2019. doi:10.3389/fphar.2019.01590. PMID 32038257. "Several close analogues of 5-chloro-αET, such as 5-chloro-αMT and 5-fluoro-αMT, are known to be potent monoamine oxidase inhibitors (MAOIs).".
↑ "Indolealkylamines and Related Compounds". Hallucinogenic Agents. Bristol: Wright-Scientechnica. 1975. pp. 98–144. ISBN 978-0-85608-011-1. OCLC 2176880. https://bitnest.netfirms.com/external/Books/978-0-85608-011-1. "[...] 5-chloro-, but not 6-chloro-, derivatives of α-methyl- and α-ethyl-tryptamine produced behavioural changes in animals (Whittle and Young, 1963); [...]"
↑ "The Synthesis and Pharmacological Activity of Some Chloro-α-alkyltryptamines". J Med Chem 6 (4): 378–380. July 1963. doi:10.1021/jm00340a009. PMID 14184890. "The synthesis of eight new monochloro analogs of a-methyl- and a-ethyltryptamines are described. These compounds were prepared by condensations of 4-, 5-, 6-, and 7-chloroindole-3-aldehydes with either nitroethane or nitropropane and subsequent reduction of the condensation products with lithium aluminum hydride. The tryptamines have been found to possess stimulant and anticonvulsant properties in rodents and to produce behavioral changes in cats. [...]".

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[BloughLandavazoPartilla2014-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 ^1.5 ^1.6 "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorg Med Chem Lett 24 (19): 4754–4758. October 2014. doi:10.1016/j.bmcl.2014.07.062. PMID 25193229. "The racemic a-alkyl tryptamines 7a, 7b, 7c, 7d, 7e, and 7f were synthesized by nitro olefin formation followed by lithium ammonium hydride reduction (Scheme 2).32 [...] a-Ethylation of the 5-chloro and 5-fluoro substituted tryptamines, to form 7e and 7f respectively, also weakened NE release activity compared to their a-methyl analogs, but 7e flipped to become a weak DA uptake inhibitor. [...] In the a-ethyltryptamine series, the 5-chloro analog (7e) and 5-fluoro analog (7f) both weakened substantially as 5-HT2A agonists compared to their a-methyl- and non-alkylated tryptamine analogs (7b/7c and 4h/4j), with EC50 values of 249 nM and 246 nM, respectively. [...] Table 1 Comparison of the DAT, SERT, and NET-mediated release activity and 5-HT2A receptor activity of substituted tryptamines [...] ^d Value is IC50 for uptake inhibition in nM.".

[Reyes-ParadaIturriaga-VasquezCassels2019-2] "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol 10. 2019. doi:10.3389/fphar.2019.01590. PMID 32038257. "Several close analogues of 5-chloro-αET, such as 5-chloro-αMT and 5-fluoro-αMT, are known to be potent monoamine oxidase inhibitors (MAOIs).".

[BrimblecombePinder1975-3] "Indolealkylamines and Related Compounds". Hallucinogenic Agents. Bristol: Wright-Scientechnica. 1975. pp. 98–144. ISBN 978-0-85608-011-1. OCLC 2176880. https://bitnest.netfirms.com/external/Books/978-0-85608-011-1. "[...] 5-chloro-, but not 6-chloro-, derivatives of α-methyl- and α-ethyl-tryptamine produced behavioural changes in animals (Whittle and Young, 1963); [...]"

[WhittleYoung1963-4] "The Synthesis and Pharmacological Activity of Some Chloro-α-alkyltryptamines". J Med Chem 6 (4): 378–380. July 1963. doi:10.1021/jm00340a009. PMID 14184890. "The synthesis of eight new monochloro analogs of a-methyl- and a-ethyltryptamines are described. These compounds were prepared by condensations of 4-, 5-, 6-, and 7-chloroindole-3-aldehydes with either nitroethane or nitropropane and subsequent reduction of the condensation products with lithium aluminum hydride. The tryptamines have been found to possess stimulant and anticonvulsant properties in rodents and to produce behavioral changes in cats. [...]".

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5-Chloro-αET

Topic: Chemistry

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