Naphthylaminopropane

Last updated

Naphthylaminopropane
Naphthylisopropylamine.svg
Clinical data
Other namesNAP; Naphthylisopropylamine; NIPA; PAL-287; Naphetamine; Amnetamine; 1-(2-Naphthyl)-2-aminopropane; beta-Methylnapthylethylamine; β-Methylnaphthylethylamine; 1-(β-Naphthyl)-2-aminopropane
Routes of
administration 		Oral
ATC code
  • None
Legal status
Legal status
  • In general: uncontrolled
Identifiers
  • 1-(Naphthalen-2-yl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C13H15N
Molar mass 185.270 g·mol−1
3D model (JSmol)
  • CC(N)Cc2ccc1ccccc1c2

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]

Contents

Pharmacology

Pharmacodynamics

Activities

Naphthylaminopropane is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). [3] [4] Its EC50 Tooltip half-maximal effective concentration 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 Tooltip maximal efficacy = 20%). [1] [2]

Naphthylaminopropane has been found to act as a potent monoamine oxidase A (MAO-A) inhibitor, with an IC50 Tooltip half-maximal inhibitory concentration 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 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 [7] [8] [9] [10] [11]
Naphthylaminopropane (NAP; PAL-287)11.112.63.4 [4] [9]
d-Methamphetamine 12.3–14.38.5–40.4736–1,292 [7] [12] [9] [11]
Methylnaphthylaminopropane (MNAP; PAL-1046)341013 [13] [14]
l-Methcathinone 13.114.81,772 [15] [10]
2-Naphthylmethcathinone (BMAPN; βk-MNAP)94% at 10 μM3427 [16] [17]
d-Ethylamphetamine 28.844.1333.0 [18] [19]
Ethylnaphthylaminopropane (ENAP; PAL-1045)13746 a12 a [13]
Phenmetrazine 29–50.470–1317,765–>10,000 [20] [9] [21] [22]
Naphthylmetrazine (PAL-704)203111RI (105) [22]
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: [23] [24]

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] [25] [26] Further research was being conducted in primates to see if the drug would be a useful substitute for treating drug addiction in humans. [27]

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. [24] 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. [28] 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. [29] [25] 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). [26] [25] Both 2-NAP and 1-NAP failed to substitute for dextroamphetamine in rodent drug discrimination tests, suggesting that they lack psychostimulant-like effects. [26] 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. [26] 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 Tooltip 6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene, and 7-AB Tooltip 7-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene. [26] [30] [31]

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] [32] Like naphthylaminopropane, these derivatives also act as potent monoamine releasing agents, including of serotonin, norepinephrine, and/or dopamine. [13] [14] [16] [32]

See also

References

  1. 1 2 3 4 Rothman RB, Blough BE, Baumann MH (December 2006). "Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction". Trends Pharmacol Sci. 27 (12): 612–618. doi:10.1016/j.tips.2006.10.006. PMID   17056126.
  2. 1 2 3 4 Rothman RB, Blough BE, Baumann MH (January 2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal. 9 (1): E1-10. doi:10.1208/aapsj0901001. PMC   2751297 . PMID   17408232.
  3. 1 2 Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (May 2005). "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. doi:10.1124/jpet.104.080101. PMID   15677348. S2CID   12135483.
  4. 1 2 3 4 5 Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, et al. (June 2005). "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. doi:10.1124/jpet.104.082503. PMID   15761112. S2CID   19802702.
  5. 1 2 Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol. 10: 1590. doi: 10.3389/fphar.2019.01590 . PMC   6989591 . PMID   32038257.
  6. ↑ Vilches-Herrera M, Miranda-Sepúlveda J, Rebolledo-Fuentes M, Fierro A, Lühr S, Iturriaga-Vasquez P, et al. (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.
  7. 1 2 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (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.
  8. ↑ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (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.
  9. 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.
  10. 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.
  11. 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.
  12. ↑ Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (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 3 4 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. 1 2 3 Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (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, et al. (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 3 4 Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, et al. (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.
  17. ↑ Yadav BJ (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. ↑ Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, et al. (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.
  19. ↑ Nicole L (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". ProQuest. 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. [...]
  20. ↑ Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, et al. (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.
  21. ↑ McLaughlin G, Baumann MH, Kavanagh PV, Morris N, Power JD, Dowling G, et al. (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.
  22. 1 2 "Phenylmorpholines and analogues thereof". Google Patents. 20 May 2011. Retrieved 7 December 2024.
  23. ↑ 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.
  24. 1 2 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.
  25. 1 2 3 Mehes G (1952). "Uber die pharmakologische wirkung vom 1-(alpha-naphtyl)-, beziehungsweise 1-(beta-naphtyl)-2-aminopropan; Beiträge zum Zuzammenhang zwischen chemischer Struktur und Wirkung" [On the pharmacological effects of 1-(alpha-naphthyl)-, and 1-(beta-naphthyl)-2-aminopropane; a contribution on the problem of chemical structure and effect]. Acta Physiologica Academiae Scientiarum Hungaricae. 3 (1): 137–151. PMID   13050439.
  26. 1 2 3 4 5 Glennon RA, Young R, Hauck AE, McKenney JD (December 1984). "Structure-activity studies on amphetamine analogs using drug discrimination methodology". Pharmacology, Biochemistry, and Behavior. 21 (6): 895–901. doi:10.1016/S0091-3057(84)80071-4. PMID   6522418. S2CID   36455297.
  27. ↑ Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB (February 2007). "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. doi:10.1124/jpet.106.107383. PMID   17071819. S2CID   8326027.
  28. ↑ Rothman RB, Baumann MH (May 2009). "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety. 8 (3): 317–329. doi:10.1517/14740330902931524. PMC   2695569 . PMID   19505264.
  29. ↑ Blicke FF, Maxwell CE (1939). "Naphthylaminoalkanes". Journal of the American Chemical Society. 61 (7): 1780–1782. Bibcode:1939JAChS..61.1780B. doi:10.1021/ja01876a039. ISSN   0002-7863.
  30. ↑ Oberlender R, Nichols DE (March 1991). "Structural variation and (+)-amphetamine-like discriminative stimulus properties". Pharmacology, Biochemistry, and Behavior. 38 (3): 581–586. doi:10.1016/0091-3057(91)90017-V. PMID   2068194. S2CID   19069907.
  31. ↑ Hathaway BA, Nichols DE, Nichols MB, Yim GK (May 1982). "A new, potent, conformationally restricted analogue of amphetamine: 2-amino-1,2-dihydronaphthalene". Journal of Medicinal Chemistry. 25 (5): 535–538. doi:10.1021/jm00347a011. PMID   6123601.
  32. 1 2 Botanas CJ, Yoon SS, de la Peña JB, Dela Peña IJ, Kim M, Woo T, et al. (January 2017). "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. doi:10.1016/j.bbr.2016.10.016. PMID   27737791.
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