Chemistry:Butylamphetamine

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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]

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 (IC50 and EC50 > 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 (EC50, nM)
Compound NE DA 5-HT 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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. 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. ↑ 2.0 2.1 2.2 2.3 "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology 245. March 2024. doi:10.1016/j.neuropharm.2023.109827. 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. ↑ 3.0 3.1 3.2 "Structure-activity relationships among some d-N-alkylated amphetamines". Pharmacol Biochem Behav 13 (6): 869–876. December 1980. 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. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  5. ↑ 5.0 5.1 5.2 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  6. ↑ 6.0 6.1 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  7. ↑ "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. March 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  8. ↑ 8.0 8.1 "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. NIDA Res Monogr. 180. 1999. pp. 1–476 (252). https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261. "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. ↑ "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. April 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  10. ↑ Nicole, Lauren (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". https://www.proquest.com/openview/a207e98868b4a9c5ac9296fb24abbcd8/. "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. ↑ "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  12. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. 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. ↑ 14.0 14.1 "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. October 1973. doi:10.1111/j.2042-7158.1973.tb09943.x. PMID 4151673. 
  15. ↑ "Metabolism of N,N-dialkylated amphetamines, including deprenyl, by CYP2D6 expressed in a human cell line". Xenobiotica 30 (3): 297–306. March 2000. 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. ↑ "Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives". Xenobiotica 29 (7): 719–732. July 1999. doi:10.1080/004982599238344. PMID 10456690. 



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