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Naphthylaminopropane

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Naphthylaminopropane
Clinical data
Other namesNAP; Naphthylisopropylamine; NIPA; PAL-287; Naphetamine; Amnetamine; 1-(2-Naphthyl)-2-aminopropane; alpha-Methylnapthylethylamine; α-Methylnaphthylethylamine; 1-(α-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
FormulaC13H15N
Molar mass185.270 g·mol−1
3D model (JSmol)
  • CC(N)Cc2ccc1ccccc1c2

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

Pharmacology

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Naphthylaminopropane acts as a non-neurotoxic releasing agent of serotonin, norepinephrine, and dopamine (i.e., as an SNDRATooltip serotonin–norepinephrine–dopamine releasing agent), with EC50Tooltip half-maximal effective concentration values for monoamine release of 3.4 nM, 11.1 nM, and 12.6 nM, respectively.[3][4] It is also an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors (EC50 = 466 nM, 40 nM, and 2.3 nM, respectively).[2] The drug acts as a full agonist of the serotonin 5-HT2B and 5-HT2A receptors and as a weak partial agonist of the serotonin 5-HT2C receptor (EmaxTooltip maximal efficacy = 20%).[1][2]

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][5][6] Further research was being conducted in primates to see if the drug would be a useful substitute for treating drug addiction in humans.[7]

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.[8] 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.[9] 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]

Naphthylaminopropane has been found to act as a potent monoamine oxidase A (MAO-A) inhibitor, with an IC50Tooltip half-maximal inhibitory concentration of 420 nM.[10][11] This is similar to the potency of the well-known MAO-A inhibitors para-methoxyamphetamine (PMA) and 4-methylthioamphetamine (4-MTA).[10]

Chemistry

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Naphthylaminopropane was first described in the scientific literature by 1939.[12][5] The drug is also known as 1-naphthylaminopropane (1-NAP) or α-naphthylaminopropane, and it was described along with its positional isomer 2-naphthylaminopropane (2-NAP; β-naphthylaminopropane).[6][5] Both 1-NAP and 2-NAP failed to substitute for dextroamphetamine in rodent drug discrimination tests, suggesting that they lack psychostimulant-like effects.[6] 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.[13]

Naphthylaminopropane is structurally related to certain rigid analogues of amphetamine.[6] Rigid amphetamine analogues include 2-aminotetralin (2-AT), 2-amino-1,2-dihydronaphthalene (2-ADN), 1-phenylpiperazine (1-PP), 2-aminoindane (2-AI), 6-ABTooltip 6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene, and 7-ABTooltip 7-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene.[6][14][15]

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).[16][17][13][18] Like naphthylaminopropane, these derivatives also act as potent monoamine releasing agents, including of serotonin, norepinephrine, and/or dopamine.[16][17][13][18]

See also

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References

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  1. ^ a b c d 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. ^ a b c 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. ^ 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. ^ a b c 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. ^ a b c 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.
  6. ^ a b c d e 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ a b 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ a b c 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ a b 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.
  17. ^ a b 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.
  18. ^ a b 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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