Naphthylaminopropane

Pharmacology

Pharmacodynamics

Activities

Naphthylaminopropane is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). Its values for induction of monoamine release are 3.4nM for serotonin, 11.1nM for norepinephrine, and 12.6nM for dopamine.

The drug is also an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. Its EC50 values are 466nM at the serotonin 5-HT2A receptor, 40nM at the serotonin 5-HT2B receptor, and 2.3nM at the serotonin 5-HT2C receptor. 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 ( = 20%).

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

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

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. 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. Notably, despite potent dopamine release induction, naphthylaminopropane produces weak or no locomotor activation in rodents.

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. 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.

Chemistry

Naphthylaminopropane was first described in the scientific literature by 1939. 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). Both 2-NAP and 1-NAP failed to substitute for dextroamphetamine in rodent drug discrimination tests, suggesting that they lack psychostimulant-like effects. 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.

Naphthylaminopropane is structurally related to certain rigid analogues of amphetamine. Rigid amphetamine analogues include 2-aminotetralin (2-AT), 2-amino-1,2-dihydronaphthalene (2-ADN), 1-phenylpiperazine (1-PP), 2-aminoindane (2-AI), , and .

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). Like naphthylaminopropane, these derivatives also act as potent monoamine releasing agents, including of serotonin, norepinephrine, and/or dopamine.

References

References

1. (December 2006). "Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction". Trends Pharmacol Sci.
2. (January 2007). "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal.
3. (May 2005). "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics.
4. (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.
5. (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol.
6. (March 2009). "Naphthylisopropylamine and N-benzylamphetamine derivatives as monoamine oxidase inhibitors". Bioorg Med Chem.
7. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse.
8. (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology.
9. (July 2008). "Dopamine Transporters: Chemistry, Biology and Pharmacology". Wiley.
10. (2017). "Neuropharmacology of New Psychoactive Substances (NPS)". Springer.
11. (1999). "Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc".
12. (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology.
13. (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.
14. Yadav, Barkha J. (16 July 2019). "Understanding Structure–Activity Relationship of Synthetic Cathinones (Bath Salts) Utilizing Methylphenidate".
15. (March 2024). "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology.
16. Nicole, Lauren. (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones".
17. (June 2002). "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology.
18. (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.
19. (20 May 2011). "Phenylmorpholines and analogues thereof".
20. (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology.
21. (1952). "Uber die pharmakologische wirkung vom 1-(alpha-naphtyl)-, beziehungsweise 1-(beta-naphtyl)-2-aminopropan; Beiträge zum Zuzammenhang zwischen chemischer Struktur und Wirkung". Acta Physiologica Academiae Scientiarum Hungaricae.
22. (December 1984). "Structure-activity studies on amphetamine analogs using drug discrimination methodology". Pharmacology, Biochemistry, and Behavior.
23. (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.
24. (August 2006). "Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs". Annals of the New York Academy of Sciences.
25. (May 2009). "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety.
26. (1939). "Naphthylaminoalkanes". Journal of the American Chemical Society.
27. (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology (Berl).
28. (March 1991). "Structural variation and (+)-amphetamine-like discriminative stimulus properties". Pharmacology, Biochemistry, and Behavior.
29. (May 1982). "A new, potent, conformationally restricted analogue of amphetamine: 2-amino-1,2-dihydronaphthalene". Journal of Medicinal Chemistry.
30. (April 2012). "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". J Pharmacol Exp Ther.
31. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend.
32. (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.