naphthylmetrazine
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| image = Naphthylmetrazine structure.png
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| class = Norepinephrine–dopamine releasing agent; Serotonin reuptake inhibitor
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| CAS_number = 1350769-57-1
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| PubChem = 54673725
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| synonyms = PAL-704; PAL704; 3-Methyl-2-(2′-naphthyl)morpholine
| IUPAC_name = 3-methyl-2-naphthalen-2-ylmorpholine
| C=15 | H=17 | N=1 | O=1
| SMILES = CC1C(OCCN1)C2=CC3=CC=CC=C3C=C2
| StdInChI = 1S/C15H17NO/c1-11-15(17-9-8-16-11)14-7-6-12-4-2-3-5-13(12)10-14/h2-7,10-11,15-16H,8-9H2,1H3
| StdInChIKey = SYFNRUAPFPQZQA-UHFFFAOYSA-N
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Naphthylmetrazine (code name PAL-704), also known as 3-methyl-2-(2′-naphthyl)morpholine, is a monoamine releasing agent (MRA) and monoamine reuptake inhibitor (MRI) of the phenylmorpholine and naphthylaminopropane families related to phenmetrazine.{{cite web | title=Phenylmorpholines and analogues thereof | website=Google Patents | date=20 May 2011 | url=https://patents.google.com/patent/WO2011146850A1/en | access-date=7 December 2024 | quote = 3-Methyl-2-(2′-Naphthyl)morpholine hydrochloride (4c, PAL 704) [...] Two of the compounds, PAL-704 and PAL-788, show unique and interesting hybrid activity in that they are DA/NE releasers, but are 5HT uptake inhibitors. [...] TABLE 4 Comparison of the DA, 5-HT, and NE Releasing Activity of a Series of Phenmetrazine Analogs [...] }}{{cite web | title=3-Methyl-2-naphthalen-2-ylmorpholine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/54673725 | access-date=16 January 2025}} It is a analogue of phenmetrazine in which the phenyl ring has been replaced with a naphthalene ring.
The drug acts as a hybrid norepinephrine–dopamine releasing agent (NDRA) and serotonin reuptake inhibitor (SRI). Its {{Abbrlink|EC50|half-maximal effective concentration}} values for induction of monoamine release are 111{{nbsp}}nM for dopamine, 203{{nbsp}}nM for norepinephrine, and inactive for serotonin in rat brain synaptosomes, whereas its {{Abbrlink|IC50|half-maximal inhibitory concentration}} for serotonin reuptake inhibition is 105{{nbsp}}nM. Hence, it is about equipotent in inducing dopamine release and inhibiting serotonin reuptake and is about 2-fold more potent in these actions than in inducing norepinephrine release.
In terms of chemical structure, naphthylmetrazine is to phenmetrazine as naphthylisopropylamine (PAL-287) is to amphetamine.{{cite journal | vauthors = Rothman RB, Blough BE, Baumann MH | title = Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions | journal = AAPS J | volume = 9 | issue = 1 | pages = E1–10 | date = January 2007 | pmid = 17408232 | pmc = 2751297 | doi = 10.1208/aapsj0901001 | url = }}{{cite journal | vauthors = Rothman RB, Blough BE, Woolverton WL, Anderson KG, Negus SS, Mello NK, Roth BL, Baumann MH | title = Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration | journal = J Pharmacol Exp Ther | volume = 313 | issue = 3 | pages = 1361–1369 | date = June 2005 | pmid = 15761112 | doi = 10.1124/jpet.104.082503 | url = }} Other naphthyl analogues of amphetamines and related compounds include methamnetamine (PAL-1046; "naphthylmethamphetamine"), ethylnaphthylaminopropane (ENAP; PAL-1045; "naphthylethylamphetamine"), BMAPN (βk-methamnetamine; "naphthylmethcathinone"), methylnaphthidate (HDMP-28; "naphthylmethylphenidate"), ethylnaphthidate (HDEP-28; "naphthylethylphenidate"), and naphyrone ("naphthyl-α-PVP" or "naphthylpyrovalerone"; O-2482).
A closely related compound to naphthylmetrazine is naphthylmorpholine (PAL-678), the naphthyl analogue of the phenmetrazine parent compound 2-phenylmorpholine (PAL-632).
References
{{Reflist}}
{{Stimulants}}
{{Monoamine releasing agents}}
{{Phenethylamines}}
Category:Beta-Hydroxyamphetamines
Category:Norepinephrine-dopamine releasing agents