Butylamphetamine

{{Short description|Amphetamine derivative and stimulant}} {{Infobox drug | drug_name = | image = Butylamphetamine.svg | image_class = skin-invert-image | width = | caption =

| legal_status =

| IUPAC_name = ''N''-(1-phenylpropan-2-yl)butan-1-amine | C=13 | H=21 | N=1 | SMILES = CCCCNC(C)CC1=CC=CC=C1 | StdInChI = 1S/C13H21N/c1-3-4-10-14-12(2)11-13-8-6-5-7-9-13/h5-9,12,14H,3-4,10-11H2,1-2H3 | StdInChIKey = VIAVBPFRYASSKF-UHFFFAOYSA-N }}

'''Butylamphetamine''' (code name '''PAL-90'''; also known as '''''N''-butylamphetamine''' or '''NBA''') is a psychostimulant of the substituted amphetamine family which was never marketed.<ref name="ReithBloughHong2015" /><ref name="FitzgeraldGannonWalther2024">{{cite journal | vauthors = Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE | title = Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones | journal = Neuropharmacology | volume = 245 | issue = | article-number = 109827 | date = March 2024 | pmid = 38154512 | doi = 10.1016/j.neuropharm.2023.109827 | pmc = 10842458 | url = | quote = Although the number of amphetamine analogues with different amine substituents is relatively low in recreational drug markets (Cho and Segal, 1994), N-methyl and N-ethyl substitutions are sometimes found. Pharmacological activity of amphetamine-type drugs is decreased substantially if the N-alkyl chain is lengthened beyond ethyl, as previous studies show that N-propylamphetamine and N-butylamphetamine are ∼4-fold and ∼6-fold less potent than amphetamine in rats (Woolverton et al., 1980).}}</ref><ref name="WoolvertonShybutJohanson1980">{{cite journal | vauthors = Woolverton WL, Shybut G, Johanson CE | title = Structure-activity relationships among some d-N-alkylated amphetamines | journal = Pharmacol Biochem Behav | volume = 13 | issue = 6 | pages = 869–876 | date = December 1980 | pmid = 7208552 | doi = 10.1016/0091-3057(80)90221-x | url = }}</ref>

It is the ''N''-butyl analogue of amphetamine<ref name="ReithBloughHong2015" /> and is approximately 6-fold less potent than amphetamine in rats.<ref name="FitzgeraldGannonWalther2024" /><ref name="WoolvertonShybutJohanson1980" /> The drug has been found to be inactive as a dopamine reuptake inhibitor or releasing agent ({{Abbrlink|IC50|half-maximal inhibitory concentration}} and {{Abbrlink|EC50|half-maximal effective concentration}} > 10,000{{nbsp}}nM, respectively).<ref name="ReithBloughHong2015">{{cite journal | vauthors = Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL | title = Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter | journal = Drug Alcohol Depend | volume = 147 | issue = | pages = 1–19 | date = February 2015 | pmid = 25548026 | pmc = 4297708 | doi = 10.1016/j.drugalcdep.2014.12.005 | url = | quote = Table 1 shows the transporter activity oftwo sets of compounds, one a set of phenethylamine (i.e., amphetamine) analogs and the other a set of β-keto phenethylamine (i.e., cathinone) analogs. Each set of compounds demonstrates predicable structural trends. Amphetamine is a DA releaser with an EC50 value of 8.7 nM. Modifications that increase the size of amphetamine gradually decreased release potency until the increases caused the activity to change to transport inhibition. Specifically, N-alkylation of amphetamine, going from no alkyl group (amphetamine) to methyl (methamphetamine) to ethyl (PAL-99) decreased EC50 values for release from 8.7 to 24.5 to 88.5 nM.Adding an additional methylene to form the N-propyl analog (PAL-424) caused the compound to become a DAT uptake inhibitor with an IC50 value of 1013 nM. Increasing the size even further to butyl (PAL-90) rendered the compound inactive at the DAT.}}</ref> With regard to structure–activity relationships, the potency of ''N''-substituted amphetamine derivatives decreases with increasing chain length in terms of both ''in vitro'' and ''in vivo'' activity.<ref name="ReithBloughHong2015" /><ref name="FitzgeraldGannonWalther2024" /><ref name="WoolvertonShybutJohanson1980" />

{| class="wikitable" style="font-size:small;" |+ {{Nowrap|Monoamine release of butylamphetamine and related agents ({{Abbrlink|EC50|Half maximal effective concentration}}, nM)}} |- ! Compound !! data-sort-type="number" | {{abbrlink|NE|Norepinephrine}} !! data-sort-type="number" | {{abbrlink|DA|Dopamine}} !! data-sort-type="number" | {{abbrlink|5-HT|Serotonin}} !! Ref |- | Phenethylamine || 10.9 || 39.5 || >10,000 || <ref name="ReithBloughHong2015" /><ref name="Forsyth2012">{{cite journal | last=Forsyth | first=Andrea N | title=Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | website=ScholarWorks@UNO | date=22 May 2012 | url=https://scholarworks.uno.edu/td/1436/ | access-date=4 November 2024}}</ref><ref name="Blough2008">{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken [NJ] | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}</ref> |- | ''d''-Amphetamine || 6.6–10.2 || 5.8–24.8 || 698–1,765 || <ref name="RothmanBaumannDersch2001">{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | s2cid = 15573624 }}</ref><ref name="BaumannPartillaLehner2013">{{cite journal | vauthors = Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW | title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products | journal = Neuropsychopharmacology | volume = 38 | issue = 4 | pages = 552–562 | date = March 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}</ref><ref name="Blough2008" /><ref name="PartillaDerschBaumann1999">{{cite book | vauthors = Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB | chapter = Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substrates | title = Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc | series = NIDA Res Monogr | volume = 180 | pages = 1–476 (252) | date = 1999 | pmid = 11680410 | doi = | url = https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261 | archive-url = https://web.archive.org/web/20230805004105/https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261 | archive-date = August 5, 2023 | quote = RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). [...] }}</ref> |- | ''d''-Methamphetamine || 12.3–14.3 || 8.5–40.4 || 736–1,292 || <ref name="RothmanBaumannDersch2001" /><ref name="BaumannAyestasPartilla2012">{{cite journal | vauthors = Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV | title = The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue | journal = Neuropsychopharmacology | volume = 37 | issue = 5 | pages = 1192–1203 | date = April 2012 | pmid = 22169943 | pmc = 3306880 | doi = 10.1038/npp.2011.304 }}</ref><ref name="Blough2008" /><ref name="PartillaDerschBaumann1999" /> |- | Ethylamphetamine || {{abbr|ND|No data}} || 88.5 || {{abbr|ND|No data}} || <ref name="ReithBloughHong2015" /> |- | {{nbsp}}{{nbsp}}''d''-Ethylamphetamine || 28.8 || 44.1 || 333.0 || <ref name="FitzgeraldGannonWalther2024" /><ref name="Nicole2022">{{cite web | last=Nicole | first=Lauren | title=In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones | date=2022 | website=ProQuest | url=https://www.proquest.com/openview/a207e98868b4a9c5ac9296fb24abbcd8/ | access-date=5 December 2024 | quote = FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]}}</ref> |- | Propylamphetamine || {{abbr|ND|No data}} || {{abbr|RI|Reuptake inhibitor}} (1,013) || {{abbr|ND|No data}} || <ref name="ReithBloughHong2015" /> |- | Butylamphetamine || {{abbr|ND|No data}} || {{abbr|IA|Inactive}} (>10,000) || {{abbr|ND|No data}} || <ref name="ReithBloughHong2015" /> |- | colspan="7" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. '''Refs:'''<ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = European Journal of Pharmacology | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 }}</ref><ref name="RothmanBaumann2006">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }}</ref> |}

The pharmacokinetics of butylamphetamine have been studied in humans.<ref name="Gorrod1973">{{cite book | last=Gorrod | first=J.W. | title=Frontiers in Catecholamine Research | chapter=The Metabolism and Excretion of 'Amphetamines' in Man | publisher=Elsevier | date=1973 | isbn=978-0-08-017922-3 | doi=10.1016/b978-0-08-017922-3.50180-5 | pages=945–950}}</ref><ref name="BeckettShenoy1973">{{cite journal | vauthors = Beckett AH, Shenoy EV | title = The effect of N-alkyl chain length of stereochemistry on the absorption, metabolism and during excretion of N-alkylamphetamines in man | journal = J Pharm Pharmacol | volume = 25 | issue = 10 | pages = 793–799 | date = October 1973 | pmid = 4151673 | doi = 10.1111/j.2042-7158.1973.tb09943.x | url = }}</ref> It can be metabolized by CYP2D6 via ring hydroxylation similarly to amphetamine.<ref name="BachCouttsBaker2000">{{cite journal | vauthors = Bach MV, Coutts RT, Baker GB | title = Metabolism of N,N-dialkylated amphetamines, including deprenyl, by CYP2D6 expressed in a human cell line | journal = Xenobiotica | volume = 30 | issue = 3 | pages = 297–306 | date = March 2000 | pmid = 10752644 | doi = 10.1080/004982500237686 | url = | quote = Ring hydroxylation was also expected because CYP2D6 can mediate the ring oxidation of other amphetamines such as N-n-butylamphetamine, N-ethylamphetamine and amphetamine (Bach et al. 1999).}}</ref><ref name="BachCouttsBaker1999">{{cite journal | vauthors = Bach MV, Coutts RT, Baker GB | title = Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives | journal = Xenobiotica | volume = 29 | issue = 7 | pages = 719–732 | date = July 1999 | pmid = 10456690 | doi = 10.1080/004982599238344 | url = }}</ref> In addition, butylamphetamine can be ''N''-dealkylated into amphetamine (6–9% excreted in urine after 24{{nbsp}}hours).<ref name="BeckettShenoy1973">{{cite journal | vauthors = Beckett AH, Shenoy EV | title = The effect of N-alkyl chain length of stereochemistry on the absorption, metabolism and during excretion of N-alkylamphetamines in man | journal = J Pharm Pharmacol | volume = 25 | issue = 10 | pages = 793–799 | date = October 1973 | pmid = 4151673 | doi = 10.1111/j.2042-7158.1973.tb09943.x | url = }}</ref>

==References== {{Reflist}}

Category:Abandoned drugs Category:Butyl compounds Category:Designer prodrugs Category:Norepinephrine-dopamine releasing agents Category:Prodrugs Category:Stimulants Category:Substituted amphetamines