Substituted naphthylethylamine

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2-Naphthylaminopropane, one of the more well-known naphthylethylamines. Naphthylisopropylamine.svg
2-Naphthylaminopropane, one of the more well-known naphthylethylamines.
1-Naphthylaminopropane, a lesser-known naphthylethylamine. 1-Naphthylaminopropane.svg
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.

Contents

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. 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 Tooltip Half maximal effective concentration, nM)
Compound NE Tooltip Norepinephrine DA Tooltip Dopamine 5-HT Tooltip SerotoninRef
d-Amphetamine 6.6–10.25.8–24.8698–1,765 [6] [7] [8] [9] [10]
1-Naphthylaminopropane NDNDNDND
2-Naphthylaminopropane (NAP; PAL-287)11.112.63.4 [11] [8]
d-Methamphetamine 12.3–14.38.5–40.4736–1,292 [6] [12] [8] [10]
Methylnaphthylaminopropane (MNAP; PAL-1046)341013 [13] [14]
l-Methcathinone 13.114.81,772 [15] [9]
1-Naphthylmethcathinone (AMAPN)92% at 10 μM5521 [2] [16]
2-Naphthylmethcathinone (BMAPN; βk-MNAP)94% at 10 μM3427 [2] [16]
d-Ethylamphetamine 28.844.1333.0 [17] [18]
Ethylnaphthylaminopropane (ENAP; PAL-1045)13746 a12 a [13]
2-Phenylmorpholine (PAL-632)798620,260 [5]
Naphthylmorpholine (PAL-678)88% at 10 μM79% at 10 μM92% at 10 μM [5]
Phenmetrazine 29–50.470–1317,765–>10,000 [19] [8] [20] [5]
Naphthylmetrazine (PAL-704)203111RI (105) [5]
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. Footnotes:a ENAP Tooltip Ethylnaphthylaminopropane is a partial releaser of serotonin (Emax Tooltip maximal efficacy = 66%) and dopamine (Emax = 78%). Refs: [21] [22]

References

  1. 1 2 3 4 5 Schmitt KC, Rothman RB, Reith ME (July 2013). "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". J Pharmacol Exp Ther. 346 (1): 2–10. doi:10.1124/jpet.111.191056. PMC   3684841 . PMID   23568856.
  2. 1 2 3 4 5 Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology (Berl). 236 (3): 915–924. doi:10.1007/s00213-018-5063-9. PMC   6475490 . PMID   30341459.
  3. 1 2 3 4 Vilches-Herrera M, Miranda-Sepúlveda J, Rebolledo-Fuentes M, Fierro A, Lühr S, Iturriaga-Vasquez P, Cassels BK, Reyes-Parada M (March 2009). "Naphthylisopropylamine and N-benzylamphetamine derivatives as monoamine oxidase inhibitors". Bioorg Med Chem. 17 (6): 2452–2460. doi:10.1016/j.bmc.2009.01.074. PMID   19243954.
  4. 1 2 3 Yoneda F, Moto T, Sakae M, Ohde H, Knoll B, Miklya I, Knoll J (May 2001). "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. doi:10.1016/s0968-0896(01)00002-5. PMID   11377178.
  5. 1 2 3 4 5 6 7 "Phenylmorpholines and analogues thereof". Google Patents. 20 May 2011. Retrieved 7 December 2024.
  6. 1 2 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707. S2CID   15573624.
  7. ↑ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC   3572453 . PMID   23072836.
  8. 1 2 3 4 Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN   978-0-470-11790-3. OCLC   181862653. OL   18589888W.
  9. 1 2 Glennon RA, Dukat M (2017). "Structure-Activity Relationships of Synthetic Cathinones". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 32: 19–47. doi:10.1007/7854_2016_41. ISBN   978-3-319-52442-9. PMC   5818155 . PMID   27830576.
  10. 1 2 Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "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 (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID   11680410. 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. ↑ Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, Roth BL, Baumann MH (June 2005). "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration". J Pharmacol Exp Ther. 313 (3): 1361–1369. doi:10.1124/jpet.104.082503. PMID   15761112.
  12. ↑ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC   3306880 . PMID   22169943.
  13. 1 2 Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE (April 2012). "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. doi:10.1124/jpet.111.188946. PMC   3364510 . PMID   22271821.
  14. ↑ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC   4297708 . PMID   25548026.
  15. ↑ Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA (October 2003). "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. doi:10.1124/jpet.103.053975. PMID   12954796. S2CID   19015584.
  16. 1 2 Yadav BJ (16 July 2019). Understanding Structure–Activity Relationship of Synthetic Cathinones (Bath Salts) Utilizing Methylphenidate (Thesis). Virginia Commonwealth University. doi:10.25772/MJQW-8C64 . Retrieved 24 November 2024– via VCU Scholars Compass.
  17. ↑ Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, Baumann MH, Fantegrossi WE (March 2024). "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology. 245: 109827. doi:10.1016/j.neuropharm.2023.109827. PMC  10842458. 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. Retrieved 5 December 2024– via ProQuest. 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. ↑ Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, Baumann MH (June 2002). "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology. 447 (1): 51–57. doi:10.1016/s0014-2999(02)01830-7. PMID   12106802.
  20. ↑ McLaughlin G, Baumann MH, Kavanagh PV, Morris N, Power JD, Dowling G, Twamley B, O'Brien J, Hessman G, Westphal F, Walther D, Brandt SD (September 2018). "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. doi:10.1002/dta.2396. PMC   7316143 . PMID   29673128.
  21. ↑ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
  22. ↑ Rothman RB, Baumann MH (August 2006). "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. Bibcode:2006NYASA1074..245R. doi:10.1196/annals.1369.064. PMID   17105921. S2CID   19739692.


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