Naphthylaminopropane

Last updated

Naphthylaminopropane
Naphthylisopropylamine.svg
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
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 that was under investigation for the treatment of alcohol and stimulant addiction. [1] [2]

Contents

Pharmacology

Pharmacodynamics

Activities

Naphthylaminopropane acts as a non-neurotoxic releasing agent of serotonin, norepinephrine, and dopamine (i.e., as an SNDRA Tooltip serotonin–norepinephrine–dopamine releasing agent), with EC50 Tooltip 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 (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]

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] [7] [8] Further research was being conducted in primates to see if the drug would be a useful substitute for treating drug addiction in humans. [9]

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. [10] 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. [11] 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. [12] [7] 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). [8] [7] Both 1-NAP and 2-NAP failed to substitute for dextroamphetamine in rodent drug discrimination tests, suggesting that they lack psychostimulant-like effects. [8] 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. [8] 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. [8] [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

Related Research Articles

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References

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  2. 1 2 3 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.
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  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 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.
  8. 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  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.
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  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. 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.
  17. 1 2 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. 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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