Chemistry:Ethylnaphthylaminopropane

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Ethylnaphthylaminopropane (ENAP; developmental code name PAL-1045) is a monoamine releasing agent (MRA) of the amphetamine and naphthylaminopropane families that is related to naphthylaminopropane (NAP; PAL-287) and methamnetamine (MNAP; PAL-1046).[1][2][3] It acts specifically as a serotonin–norepinephrine–dopamine releasing agent (SNDRA).[2][3] However, ENAP is unusual in being a partial releaser of serotonin and dopamine and a full releaser of norepinephrine.[1][2][3]

The EC50 (Emax) values of ENAP in terms of monoamine release induction are 12 nM (66%) for serotonin, 46 nM (78%) for dopamine, and 137 nM (94%) for norepinephrine in rat brain synaptosomes.[2][3] In contrast to NAP and MNAP, which produce clearly dose-dependent increases in locomotor stimulation and brain monoamine levels in rodents, ENAP has been found to show attenuated monoamine elevations and a "flat" dose–response curve.[4][3] Relatedly, it may have less misuse liability than other drugs like amphetamine, although more research is necessary to assess this possibility.[4][3]

In addition to its MRA activity, ENAP has been found to be an effective pharmacological chaperone for rescuing misfolded mutant monoamine transporters (MATs).[5][6]

Monoamine release of ethylnaphthylaminopropane 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 [12][9]
d-Methamphetamine 12.3–14.3 8.5–40.4 736–1,292 [7][13][9][11]
Methylnaphthylaminopropane (MNAP; PAL-1046) 34 10 13 [3][2]
l-Methcathinone 13.1 14.8 1,772 [14][10]
2-Naphthylmethcathinone (BMAPN; βk-MNAP) 94% at 10 μM 34 27 [15][16]
d-Ethylamphetamine 28.8 44.1 333.0 [17][18]
Ethylnaphthylaminopropane (ENAP; PAL-1045) 137 46 a 12 a [3]
Phenmetrazine 29–50.4 70–131 7,765–>10,000 [19][9][20][21]
Naphthylmetrazine (PAL-704) 203 111 RI (105) [21]

See also

References

  1. ↑ 1.0 1.1 "Molecular Mechanisms of Amphetamines". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 258: 265–297. 2020. doi:10.1007/164_2019_251. ISBN 978-3-030-33678-3. PMID 31286212. "Other anti-amphetamine agents in preclinical research are the "partial substrates" also called "partial releasers." In a large series of phenethylamine structures, Blough and colleagues (see Reith et al. 2015) observed that upon increasing size, substrate releaser activity converted to uptake inhibition; as the increasing size of the phenethylamine structure nears the edge of the pharmacophore, the releasing potency weakens even before the compound becomes an uptake inhibitor. It is in this structural border region where we find the partial releasers. Thus, PAL-1045 (N-ethyl-naphtylaminopropane or ENAP) and PAL-193 (3,4-methylenedioxy-Nethylamphetamine), rather than being substrates with full releasing capability, released no more than 78% and 61%, respectively, of preloaded [3 H]MPP+ from rat synaptosomes (Rothman et al. 2012; Reith et al. 2015). PAL-1045, as bupropion, stabilizes inward conformations of monoamine transporters but, unlike bupropion, is still a substrate (Bhat et al. 2017 and see below final paragraph of this section). Whereas the full releaser 2-naphthyl analog of amphetamine, NAP, dosedependently increased accumbal dialysate DA, PAL-1045 showed a low-efficacy flat dose-response curve (Rothman et al. 2012) in accordance with its partial releasing character.". 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "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. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 "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. 
  4. ↑ 4.0 4.1 "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. "Another line of evidence for the selective modulation of reverse transport comes from our recent report that different DAT substrates can have variable efficacies for inducing DAT-mediated efflux of the labeled substrate [3H]MPP+. For example, whereas the full substrate naphthylaminopropane (NAP, the (2-naphthyl)-analog of amphetamine, also known as PAL-278; see Fig. 2A for structure) produced complete efflux of preloaded [3H]MPP+ from rat synaptosomes within 30 minutes (Emax, ∼100%), N-ethyl-naphthylaminopropane (ENAP, also known as PAL-1045; Fig. 2B) was unable to elicit complete [3H]MPP+ release within the experimental period (efflux reached a plateau, with Emax = 78%). Similarly, although the empathogen 3,4-methylenedioxyamphetamine is a full DAT substrate (Rothman et al., 2009), the ethyl analog 3,4-methylenedioxy-N-ethylamphetamine behaved as a partial substrate, with an Emax value of roughly 65%. Of importance, the plateau in transporter-mediated [3H]MPP+ efflux was insurmountable; merely increasing the concentration of a partial substrate did not produce complete release. In addition, the attenuated response observed for partial substrates in [3H]MPP+ release assays was also demonstrated in vivo: whereas NAP produced clear dose-dependent increases in locomotor stimulation and extraneuronal DA levels in rats, ENAP showed a flat dose-response curve (Rothman et al., 2012). However, the question of whether the attenuated monoamine-releasing effect of partial substrates, such as ENAP, is genuinely consequential in vivo will require further tests of such compounds in relevant behavioral assays, such as self-administration, drug discrimination, and conditioned place preference.". 
  5. ↑ "How to rescue misfolded SERT, DAT and NET: targeting conformational intermediates with atypical inhibitors and partial releasers". Biochem Soc Trans 47 (3): 861–874. June 2019. doi:10.1042/BST20180512. PMID 31064865. 
  6. ↑ "SLC6 Transporter Folding Diseases and Pharmacochaperoning". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 245: 249–270. 2018. doi:10.1007/164_2017_71. ISBN 978-3-319-74163-5. PMID 29086036. 
  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. ↑ "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. 
  13. ↑ "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. 
  14. ↑ "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. 
  15. ↑ "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. 
  16. ↑ 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.
  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, 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. [...]" 
  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. 
  21. ↑ 21.0 21.1 "Phenylmorpholines and analogues thereof". 20 May 2011. https://patents.google.com/patent/WO2011146850A1/en. 



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