Naphthylaminopropane Explained

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-HT_2A, 5-HT_2B, and 5-HT_2C receptors (EC₅₀ values = 466 nM, 40 nM, and 2.3 nM, respectively),^[1] and acts as a full agonist at 5-HT_2B and as a partial agonist at 5-HT_2C, while its affinity for 5-HT_2A 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 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-HT_2C 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 5HT_2B 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 5HT_2A and 5HT_2B 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.

See also

• 5-APDI
• 6-APT
• HDEP-28
• HDMP-28
• Methamnetamine, N-methyl analogue, codenamed "MY-10" according to (Table 2).
• Naphyrone

Notes and References

1. Rothman RB, Blough BE, Baumann MH. Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions . The AAPS Journal . 9 . 1 . E1-10 . January 2007 . 17408232 . 2751297 . 10.1208/aapsj0901001 .
2. Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, Roth BL, Baumann MH . 6 . 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 . June 2005 . 15761112 . 10.1124/jpet.104.082503 . 19802702 .
3. Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL . 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 . May 2005 . 15677348 . 10.1124/jpet.104.080101 . 12135483 .
4. Mehes G . [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 . 1952 . 13050439 .
5. Glennon RA, Young R, Hauck AE, McKenney JD . Structure-activity studies on amphetamine analogs using drug discrimination methodology . Pharmacology, Biochemistry, and Behavior . 21 . 6 . 895–901 . December 1984 . 6522418 . 10.1016/S0091-3057(84)80071-4 . 36455297 .
6. Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB . 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 . February 2007 . 17071819 . 10.1124/jpet.106.107383 . 8326027 .
7. Rothman RB, Baumann MH . 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 . August 2006 . 17105921 . 10.1196/annals.1369.064 . 2006NYASA1074..245R . 19739692 .
8. Rothman RB, Baumann MH . Serotonergic drugs and valvular heart disease . Expert Opinion on Drug Safety . 8 . 3 . 317–29 . May 2009 . 19505264 . 2695569 . 10.1517/14740330902931524 .
9. Baumann MH, Rothman RB . Neural and cardiac toxicities associated with 3,4-methylenedioxymethamphetamine (MDMA) . International Review of Neurobiology . 88 . 257–96 . 2009 . 19897081 . 3153986 . 10.1016/S0074-7742(09)88010-0 . 978-0-12-374504-0 .