Naphthylaminopropane

Naphthylaminopropane
Clinical data
Other names1-(2-naphthyl)-2-aminopropane; alpha-methylnapthylethylamine
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 (PAL-287) is an experimental drug under investigation as of 2007 for the treatment of alcohol and stimulant addiction.[1]

Naphthylisopropylamine acts as a non-neurotoxic[2] releasing agent of serotonin, norepinephrine, and dopamine, with EC50 values of 3.4 nM, 11.1 nM, and 12.6 nM, respectively.[3] It also has affinity for the 5-HT2A, 5-HT2B, and 5-HT2C receptors (EC50 values = 466 nM, 40 nM, and 2.3 nM, respectively),[1] and acts as a full agonist at 5-HT2B and as a partial agonist at 5-HT2C, while its affinity for 5-HT2A is probably too low to be significant.[1]

In animal studies, naphthylisopropylamine was shown to reduce cocaine self-administration, yet produced relatively weak stimulant effects when administered alone, being a (much) lesser stimulant than d-amphetamine for comparison.[2][4][5] Further research is now[when?] being conducted in primates to see if it will be a useful substitute for treating drug addiction in humans as well.[6]

An important observation is that in behavioral studies, rodents would consistently self-administer selective norepinephrine and dopamine releasing agents such as d-amphetamine, yet compounds that also release serotonin like naphthylisopropylamine would not be self-administered.[2] In addition to the drugs (acute) effects on self-administration, all of the available evidence suggests that the locomotor activation caused by the majority of dopamine releasers is also dampened when the drugs also cause serotonergic release.[7] In fact, PAL-287 causes no locomotor activation at all (although admittedly the tests were only after acute dosing).

The high affinity of PAL-287 for 5-HT2C receptors meant that it functioned as a reliable anorectant and was being considered for this indication (i.e., weight loss). However, there were ultimately some concerns raised over the affinity of the compounds for 5HT2B receptors, since some of the more serious side effects of the serotonin-releasing weight loss drug fenfluramine were linked to activation of this receptor.[8] Apparently, more research will have to be done to assess if PAL-287 causes activation of the 5HT2A and 5HT2B receptors in vivo. However, according to the authors, even the relatively safe drug MDMA causes heart disease,[9] and the incidence being reported for fenfluramine was not that great, even though the evidence being presented was indisputable.[8] Thus it is relatively more likely that any of the more serious side effects from using PAL-287 will only occur in cases of overdose, and not when using a clinically responsible amount of the drug.

  1. ^ 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.
  2. ^ 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): 1361–9. doi:10.1124/jpet.104.082503. PMID 15761112. S2CID 19802702.
  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): 848–54. doi:10.1124/jpet.104.080101. PMID 15677348. S2CID 12135483.
  4. ^ Mehes G (1952). "[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): 137–51. PMID 13050439.
  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.
  6. ^ 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): 627–36. doi:10.1124/jpet.106.107383. PMID 17071819. S2CID 8326027.
  7. ^ 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): 245–60. Bibcode:2006NYASA1074..245R. doi:10.1196/annals.1369.064. PMID 17105921. S2CID 19739692.
  8. ^ a b Rothman RB, Baumann MH (May 2009). "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety. 8 (3): 317–29. doi:10.1517/14740330902931524. PMC 2695569. PMID 19505264.
  9. ^ Baumann MH, Rothman RB (2009). "Neural and cardiac toxicities associated with 3,4-methylenedioxymethamphetamine (MDMA)". International Review of Neurobiology. 88: 257–96. doi:10.1016/S0074-7742(09)88010-0. ISBN 978-0-12-374504-0. PMC 3153986. PMID 19897081.