Chemistry:Naphthylmorpholine

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Naphthylmorpholine (code name PAL-678), also known as 2-(2′-naphthyl)morpholine, is a monoamine releasing agent of the arylmorpholine and naphthylethylamine families.[1][2] It is the derivative of 2-phenylmorpholine with a 2-naphthalene ring instead of a phenyl ring.[1][2] Naphthylmorpholine is a close analogue of naphthylmetrazine (PAL-704; a naphthalene analogue of phenmetrazine), but lacks naphthylmetrazine's methyl group at the 3 position of the morpholine ring.[1][2]

The drug is a potent monoamine releasing agent.[1] Its EC50 values for induction of monoamine release have not been reported, but it released 92% of serotonin, 88% of norepinephrine, and 79% of dopamine at a concentration of 10,000 nM in rat brain synaptosomes.[1] Hence, it appears to act preferentially as a releaser of serotonin and norepinephrine and to a lesser extent of dopamine.[1]

Monoamine release of naphthylmorpholine and related agents (EC50, nM)
Compound NE DA 5-HT Ref
d-Amphetamine 6.6–10.2 5.8–24.8 698–1,765 [3][4][5][6][7]
Naphthylaminopropane (NAP; PAL-287) 11.1 12.6 3.4 [8][5]
d-Methamphetamine 12.3–14.3 8.5–40.4 736–1,292 [3][9][5][7]
Methylnaphthylaminopropane (MNAP; PAL-1046) 34 10 13 [10][11]
l-Methcathinone 13.1 14.8 1,772 [12][6]
2-Naphthylmethcathinone (BMAPN; βk-MNAP) 94% at 10 μM 34 27 [13][14]
d-Ethylamphetamine 28.8 44.1 333.0 [15][16]
Ethylnaphthylaminopropane (ENAP; PAL-1045) 137 46 a 12 a [10]
2-Phenylmorpholine (PAL-632) 79 86 20,260 [1]
Naphthylmorpholine (PAL-678) 88% at 10 μM 79% at 10 μM 92% at 10 μM [1]
Phenmetrazine 29–50.4 70–131 7,765–>10,000 [17][5][18][1]
Naphthylmetrazine (PAL-704) 203 111 RI (105) [1]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 "Phenylmorpholines and analogues thereof". 20 May 2011. https://patents.google.com/patent/WO2011146850A1/en. "3-Methyl-2-(2′-Naphthyl)morpholine hydrochloride (4c, PAL 704) [...] Two of the compounds, PAL-704 and PAL-788, show unique and interesting hybrid activity in that they are DA/NE releasers, but are 5HT uptake inhibitors. [...] TABLE 4 Comparison of the DA, 5-HT, and NE Releasing Activity of a Series of Phenmetrazine Analogs [...]" 
  2. ↑ 2.0 2.1 2.2 "2-(Naphthalen-2-yl)morpholine". https://pubchem.ncbi.nlm.nih.gov/compound/43350792. 
  3. ↑ 3.0 3.1 "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. 
  4. ↑ "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. 
  5. ↑ 5.0 5.1 5.2 5.3 "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. 
  6. ↑ 6.0 6.1 "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. 
  7. ↑ 7.0 7.1 "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." 
  8. ↑ "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. 
  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. ↑ 10.0 10.1 "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. 
  11. ↑ "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. 
  12. ↑ "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. 
  13. ↑ "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. 
  14. ↑ 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.
  15. ↑ "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. 
  16. ↑ 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. [...]
  17. ↑ "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. 
  18. ↑ "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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