Chemistry:Substituted naphthylethylamine

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Short description: Class of chemical compounds
2-Naphthylaminopropane, one of the more well-known naphthylethylamines.
1-Naphthylaminopropane, a lesser-known naphthylethylamine.

The substituted naphthylethylamines are a class of chemical compounds based on naphthalene. Many naphthylethylamines are naphthylaminopropanes (also known as naphthylisopropylamines) due to the presence of a methyl group at the alpha carbon of the alkyl chain. The naphthylethylamines are derivatives of the phenethylamines, while the naphthylaminopropanes are derivatives of the amphetamines.

There are two types of naphthylethylamines based on positional isomerism: 1-naphthylethylamines and 2-naphthylethylamines. Examples of these include 1-naphthylaminopropane (1-NAP) and 2-naphthylaminopropane (2-NAP), respectively.

List of substituted naphthylethylamines

The substituted napthylethylamines include the following compounds:[1][2][3]

Additional naphthylethylamines include 4-NEMD, centanafadine (EB-1020), nafimidone, naphazoline, and xaliproden (SR-57746). Some synthetic cannabinoids such as THJ-018 and THJ-2201 are also naphthylethylamines.

Some related compounds that are not technically naphthylethylamines include 1-naphthylpiperazine and its derivatives like CSP-2503, F-11,461, S-14506, and S-14671. Another related compound is 2-naphthylpiperazine. DMNPC is a 2-naphthylpiperidine.

Pharmacology

Many naphthylethylamines, like 2-naphthylaminopropane and derivatives, act as monoamine releasing agents (MRAs), monoamine reuptake inhibitors (MRIs), and/or monoamine receptor modulators.[1][5] Naphthylpropylaminopentane (NPAP) is a monoaminergic activity enhancer (MAE).[4] Some, such as 2-naphthylaminopropane and to a lesser extent 1-naphthylaminopropane, but not others, such as NPAP, are also variably potent monoamine oxidase inhibitors (MAOIs).[3][4]

Monoamine release of naphthylethylamines (EC50, nM)
Compound NE DA 5-HT Ref
d-Amphetamine 6.6–10.2 5.8–24.8 698–1,765 [6][7][8][9][10]
1-Naphthylaminopropane ND ND ND ND
2-Naphthylaminopropane (NAP; PAL-287) 11.1 12.6 3.4 [11][8]
d-Methamphetamine 12.3–14.3 8.5–40.4 736–1,292 [6][12][8][10]
Methylnaphthylaminopropane (MNAP; PAL-1046) 34 10 13 [13][14]
l-Methcathinone 13.1 14.8 1,772 [15][9]
1-Naphthylmethcathinone (AMAPN) 92% at 10 μM 55 21 [2][16]
2-Naphthylmethcathinone (BMAPN; βk-MNAP) 94% at 10 μM 34 27 [2][16]
d-Ethylamphetamine 28.8 44.1 333.0 [17][18]
Ethylnaphthylaminopropane (ENAP; PAL-1045) 137 46 a 12 a [13]
2-Phenylmorpholine (PAL-632) 79 86 20,260 [5]
Naphthylmorpholine (PAL-678) 88% at 10 μM 79% at 10 μM 92% at 10 μM [5]
Phenmetrazine 29–50.4 70–131 7,765–>10,000 [19][8][20][5]
Naphthylmetrazine (PAL-704) 203 111 RI (105) [5]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". J Pharmacol Exp Ther 346 (1): 2–10. July 2013. doi:10.1124/jpet.111.191056. PMID 23568856. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology (Berl) 236 (3): 915–924. March 2019. doi:10.1007/s00213-018-5063-9. PMID 30341459. 
  3. ↑ 3.0 3.1 3.2 3.3 "Naphthylisopropylamine and N-benzylamphetamine derivatives as monoamine oxidase inhibitors". Bioorg Med Chem 17 (6): 2452–2460. March 2009. doi:10.1016/j.bmc.2009.01.074. PMID 19243954. 
  4. ↑ 4.0 4.1 4.2 "Structure-activity studies leading to (-)1-(benzofuran-2-yl)-2-propylaminopentane, ((-)BPAP), a highly potent, selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain". Bioorganic & Medicinal Chemistry 9 (5): 1197–1212. May 2001. doi:10.1016/s0968-0896(01)00002-5. PMID 11377178. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Phenylmorpholines and analogues thereof". 20 May 2011. https://patents.google.com/patent/WO2011146850A1/en. 
  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 8.2 8.3 "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. 
  9. ↑ 9.0 9.1 "Structure-Activity Relationships of Synthetic Cathinones". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. 32. Springer. 2017. pp. 19–47. doi:10.1007/7854_2016_41. ISBN 978-3-319-52442-9. 
  10. ↑ 10.0 10.1 "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). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays." 
  11. ↑ "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration". J Pharmacol Exp Ther 313 (3): 1361–1369. June 2005. doi:10.1124/jpet.104.082503. PMID 15761112. 
  12. ↑ "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. 
  13. ↑ 13.0 13.1 "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". J Pharmacol Exp Ther 341 (1): 251–262. April 2012. doi:10.1124/jpet.111.188946. PMID 22271821. 
  14. ↑ "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. 
  15. ↑ "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". The Journal of Pharmacology and Experimental Therapeutics 307 (1): 138–145. October 2003. doi:10.1124/jpet.103.053975. PMID 12954796. 
  16. ↑ 16.0 16.1 Yadav BJ (16 July 2019). Understanding Structure–Activity Relationship of Synthetic Cathinones (Bath Salts) Utilizing Methylphenidate. Theses and Dissertations (Thesis). Virginia Commonwealth University. doi:10.25772/MJQW-8C64. Retrieved 24 November 2024 – via VCU Scholars Compass.
  17. ↑ "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. 
  18. ↑ Nicole L (2022). In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones (Ph.D. thesis). University of Arkansas for Medical Sciences. ProQuest 2711781450. 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. [...]
  19. ↑ "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology 447 (1): 51–57. June 2002. doi:10.1016/s0014-2999(02)01830-7. PMID 12106802. 
  20. ↑ "Synthesis, analytical characterization, and monoamine transporter activity of the new psychoactive substance 4-methylphenmetrazine (4-MPM), with differentiation from its ortho- and meta- positional isomers". Drug Test Anal 10 (9): 1404–1416. September 2018. doi:10.1002/dta.2396. PMID 29673128. 

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