Chemistry:Naphthylaminopropane

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Naphthylaminopropane (NAP; code name PAL-287), also known as naphthylisopropylamine (NIPA), is an experimental drug of the amphetamine and naphthylaminopropane families that was under investigation for the treatment of alcohol and stimulant addiction.[1][2]

Pharmacology

Pharmacodynamics

Activities

Naphthylaminopropane is a serotonin–norepinephrine–dopamine releasing agent (SNDRA).[3][4] Its EC50 values for induction of monoamine release are 3.4 nM for serotonin, 11.1 nM for norepinephrine, and 12.6 nM for dopamine.[3][4]

The drug is also an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors.[2] Its EC50 values are 466 nM at the serotonin 5-HT2A receptor, 40 nM at the serotonin 5-HT2B receptor, and 2.3 nM at the serotonin 5-HT2C receptor.[2] It is a full agonist of the serotonin 5-HT2A and 5-HT2B receptors and a weak partial agonist of the serotonin 5-HT2C receptor (Emax = 20%).[1][2]

Naphthylaminopropane has been found to act as a potent monoamine oxidase A (MAO-A) inhibitor, with an IC50 of 420 nM.[5][6] This is similar to the potency of the well-known MAO-A inhibitors para-methoxyamphetamine (PMA) and 4-methylthioamphetamine (4-MTA).[5]

Monoamine release of naphthylaminopropane and related agents (EC50, nM)
Compound NE DA 5-HT Ref
d-Amphetamine 6.6–10.2 5.8–24.8 698–1,765 [7][8][9][10][11]
Naphthylaminopropane (NAP; PAL-287) 11.1 12.6 3.4 [4][9]
d-Methamphetamine 12.3–14.3 8.5–40.4 736–1,292 [7][12][9][11]
Methylnaphthylaminopropane (MNAP; PAL-1046) 34 10 13 [13][14]
l-Methcathinone 13.1 14.8 1,772 [15][10]
2-Naphthylmethcathinone (BMAPN; βk-MNAP) 94% at 10 μM 34 27 [16][17]
d-Ethylamphetamine 28.8 44.1 333.0 [18][19]
Ethylnaphthylaminopropane (ENAP; PAL-1045) 137 46 a 12 a [13]
Phenmetrazine 29–50.4 70–131 7,765–>10,000 [20][9][21][22]
Naphthylmetrazine (PAL-704) 203 111 RI (105) [22]

Effects

In animal studies, naphthylaminopropane was shown to reduce cocaine self-administration, yet produced relatively weak stimulant effects when administered alone, being a much less effective stimulant than dextroamphetamine.[4][23][24] Further research was being conducted in primates to see if the drug would be a useful substitute for treating drug addiction in humans.[25]

An important observation is that in behavioral studies, rodents would consistently self-administer selective norepinephrine–dopamine releasing agents (NDRAs) like dextroamphetamine, yet compounds that also potently release serotonin like naphthylaminopropane would not be self-administered.[4] In addition to the drug's effects on self-administration, the available evidence suggests that the locomotor activation caused by dopamine releasers is also dampened when they additionally induce serotonin release.[26] Notably, despite potent dopamine release induction, naphthylaminopropane produces weak or no locomotor activation in rodents.[1]

The high affinity of naphthylaminopropane for the serotonin 5-HT2C receptor meant that it might function as an appetite suppressant and was being considered for possible clinical use for this indication (i.e., weight loss). However, concerns were raised over the affinity of the drug for the serotonin 5-HT2B receptor, since some of the more serious side effects of the serotonin-releasing weight loss drug fenfluramine were linked to activation of this receptor.[27] It is uncertain, although was considered unlikely per the researchers who developed the drug, that activation of the serotonin 5-HT2A and 5-HT2B receptors occurs to a significant degree in vivo.[1]

Chemistry

Naphthylaminopropane was first described in the scientific literature by 1939.[28][23] The drug is also known as 2-naphthylaminopropane (2-NAP) or β-naphthylaminopropane, and it was described along with its positional isomer 1-naphthylaminopropane (1-NAP; α-naphthylaminopropane).[24][23] Both 2-NAP and 1-NAP failed to substitute for dextroamphetamine in rodent drug discrimination tests, suggesting that they lack psychostimulant-like effects.[24] The β-keto and N-methyl analogue of 2-NAP has been assessed and was found to act as a potent SNDRA similarly to naphthylaminopropane.[16]

Naphthylaminopropane is structurally related to certain rigid analogues of amphetamine.[24] Rigid amphetamine analogues include 2-aminotetralin (2-AT), 2-amino-1,2-dihydronaphthalene (2-ADN), 1-phenylpiperazine (1-PP), 2-aminoindane (2-AI), 6-AB, and 7-AB.[24][29][30]

A few derivatives of naphthylaminopropane have been developed or have appeared, including methamnetamine (N-methylnaphthylaminopropane; MNAP; PAL-1046), N-ethylnaphthylaminopropane (ENAP; PAL-1045), and BMAPN (βk-methamnetamine; β-keto-MNAP; 2-naphthylmethcathinone).[13][14][16][31] Like naphthylaminopropane, these derivatives also act as potent monoamine releasing agents, including of serotonin, norepinephrine, and/or dopamine.[13][14][16][31]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction". Trends Pharmacol Sci 27 (12): 612–618. December 2006. doi:10.1016/j.tips.2006.10.006. PMID 17056126. 
  2. ↑ 2.0 2.1 2.2 2.3 "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal 9 (1): E1-10. January 2007. doi:10.1208/aapsj0901001. PMID 17408232. 
  3. ↑ 3.0 3.1 "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics 313 (2): 848–854. May 2005. doi:10.1124/jpet.104.080101. PMID 15677348. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration". The Journal of Pharmacology and Experimental Therapeutics 313 (3): 1361–1369. June 2005. doi:10.1124/jpet.104.082503. PMID 15761112. 
  5. ↑ 5.0 5.1 "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol 10. 2019. doi:10.3389/fphar.2019.01590. PMID 32038257. 
  6. ↑ "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. http://americanae.aecid.es/americanae/es/registros/registro.do?tipoRegistro=MTD&idBib=3268134. 
  7. ↑ 7.0 7.1 "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. 
  8. ↑ "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. 
  9. ↑ 9.0 9.1 9.2 9.3 "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. 
  10. ↑ 10.0 10.1 "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. 
  11. ↑ 11.0 11.1 "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." 
  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 13.2 13.3 "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. ↑ 14.0 14.1 14.2 "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 16.2 16.3 "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. 
  17. ↑ Yadav, Barkha J (16 July 2019). Understanding Structure–Activity Relationship of Synthetic Cathinones (Bath Salts) Utilizing Methylphenidate. VCU Scholars Compass (Thesis). doi:10.25772/MJQW-8C64. Retrieved 24 November 2024.
  18. ↑ "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. 
  19. ↑ 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. [...]" 
  20. ↑ "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. 
  21. ↑ "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. 
  22. ↑ 22.0 22.1 "Phenylmorpholines and analogues thereof". 20 May 2011. https://patents.google.com/patent/WO2011146850A1/en. 
  23. ↑ 23.0 23.1 23.2 "Uber die pharmakologische wirkung vom 1-(alpha-naphtyl)-, beziehungsweise 1-(beta-naphtyl)-2-aminopropan; Beiträge zum Zuzammenhang zwischen chemischer Struktur und Wirkung". Acta Physiologica Academiae Scientiarum Hungaricae 3 (1): 137–151. 1952. PMID 13050439. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 "Structure-activity studies on amphetamine analogs using drug discrimination methodology". Pharmacology, Biochemistry, and Behavior 21 (6): 895–901. December 1984. doi:10.1016/S0091-3057(84)80071-4. PMID 6522418. 
  25. ↑ "Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys". The Journal of Pharmacology and Experimental Therapeutics 320 (2): 627–636. February 2007. doi:10.1124/jpet.106.107383. PMID 17071819. 
  26. ↑ "Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs". Annals of the New York Academy of Sciences 1074 (1): 245–260. August 2006. doi:10.1196/annals.1369.064. PMID 17105921. Bibcode: 2006NYASA1074..245R. 
  27. ↑ "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety 8 (3): 317–329. May 2009. doi:10.1517/14740330902931524. PMID 19505264. 
  28. ↑ "Naphthylaminoalkanes". Journal of the American Chemical Society 61 (7): 1780–1782. 1939. doi:10.1021/ja01876a039. ISSN 0002-7863. Bibcode: 1939JAChS..61.1780B. 
  29. ↑ "Structural variation and (+)-amphetamine-like discriminative stimulus properties". Pharmacology, Biochemistry, and Behavior 38 (3): 581–586. March 1991. doi:10.1016/0091-3057(91)90017-V. PMID 2068194. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=77437efa02b4a0f688e4038b153ddfafde6da614. 
  30. ↑ "A new, potent, conformationally restricted analogue of amphetamine: 2-amino-1,2-dihydronaphthalene". Journal of Medicinal Chemistry 25 (5): 535–538. May 1982. doi:10.1021/jm00347a011. PMID 6123601. 
  31. ↑ 31.0 31.1 "A novel synthetic cathinone, 2-(methylamino)-1-(naphthalen-2-yl) propan-1-one (BMAPN), produced rewarding effects and altered striatal dopamine-related gene expression in mice". Behav Brain Res 317: 494–501. January 2017. doi:10.1016/j.bbr.2016.10.016. PMID 27737791. 

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