Butylamphetamine

Butylamphetamine (code name PAL-90; also known as N-butylamphetamine or NBA) is a psychostimulant of the substituted amphetamine family which was never marketed.^[1][2][3]

Butylamphetamine

Clinical data
Other names	N-Butylamphetamine; N-(n-Butyl)amphetamine; NBA; PAL-90; 1-Phenyl-2-butylaminopropane; N-Butyl-α-methylphenethylamine
Identifiers
IUPAC name N-(1-phenylpropan-2-yl)butan-1-amine
CAS Number	51799-33-8
PubChem CID	94547
ChemSpider	85320
ChEMBL	ChEMBL1907545
Chemical and physical data
Formula	C13H21N
Molar mass	191.318 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCCCNC(C)CC1=CC=CC=C1
InChI InChI=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 Key:VIAVBPFRYASSKF-UHFFFAOYSA-N

It is the N-butyl analogue of amphetamine^[1] and is approximately 6-fold less potent than amphetamine in rats.^[2][3] The drug has been found to be inactive as a dopamine reuptake inhibitor or releasing agent (IC₅₀Tooltip half-maximal inhibitory concentration and EC₅₀Tooltip half-maximal effective concentration > 10,000 nM, respectively).^[1] 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.^[1][2][3]

Monoamine release of butylamphetamine and related agents (EC₅₀Tooltip Half maximal effective concentration, nM)

Compound	NETooltip Norepinephrine	DATooltip Dopamine	5-HTTooltip Serotonin	Ref
Phenethylamine	10.9	39.5	>10,000	[1][4][5]
d-Amphetamine	6.6–10.2	5.8–24.8	698–1,765	[6][7][5][8]
d-Methamphetamine	12.3–14.3	8.5–40.4	736–1,292	[6][9][5][8]
Ethylamphetamine	ND	88.5	ND	[1]
d-Ethylamphetamine	28.8	44.1	333.0	[2][10]
Propylamphetamine	ND	RI (1,013)	ND	[1]
Butylamphetamine	ND	IA (>10,000)	ND	[1]
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: [11][12]

The pharmacokinetics of butylamphetamine have been studied in humans.^[13][14] It can be metabolized by CYP2D6 via ring hydroxylation similarly to amphetamine.^[15][16] In addition, butylamphetamine can be N-dealkylated into amphetamine (6–9% excreted in urine after 24 hours).^[14]

See also

• Methamphetamine
• Ethylamphetamine
• Propylamphetamine
• Isopropylamphetamine

References

1. Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026. 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.
2. Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE (March 2024). "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology. 245: 109827. doi:10.1016/j.neuropharm.2023.109827. PMC 10842458. PMID 38154512. 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).
3. Woolverton WL, Shybut G, Johanson CE (December 1980). "Structure-activity relationships among some d-N-alkylated amphetamines". Pharmacol Biochem Behav. 13 (6): 869–876. doi:10.1016/0091-3057(80)90221-x. PMID 7208552.
4. Forsyth, Andrea N (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
5. Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W.
6. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624.
7. 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 (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC 3572453. PMID 23072836.
8. Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID 11680410. 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). [...]
9. Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC 3306880. PMID 22169943.
10. Nicole, Lauren (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". ProQuest. Retrieved 5 December 2024. 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. [...]
11. Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
12. Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
13. Gorrod, J.W. (1973). "The Metabolism and Excretion of 'Amphetamines' in Man". Frontiers in Catecholamine Research. Elsevier. pp. 945–950. doi:10.1016/b978-0-08-017922-3.50180-5. ISBN 978-0-08-017922-3.
14. Beckett AH, Shenoy EV (October 1973). "The effect of N-alkyl chain length of stereochemistry on the absorption, metabolism and during excretion of N-alkylamphetamines in man". J Pharm Pharmacol. 25 (10): 793–799. doi:10.1111/j.2042-7158.1973.tb09943.x. PMID 4151673.
15. Bach MV, Coutts RT, Baker GB (March 2000). "Metabolism of N,N-dialkylated amphetamines, including deprenyl, by CYP2D6 expressed in a human cell line". Xenobiotica. 30 (3): 297–306. doi:10.1080/004982500237686. PMID 10752644. 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).
16. Bach MV, Coutts RT, Baker GB (July 1999). "Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives". Xenobiotica. 29 (7): 719–732. doi:10.1080/004982599238344. PMID 10456690.