Naphthylmetrazine

Naphthylmetrazine
Clinical data
Other namesPAL-704; PAL704; 3-Methyl-2-(2′-naphthyl)morpholine
Drug classNorepinephrine–dopamine releasing agent; Serotonin reuptake inhibitor
Identifiers
  • 3-methyl-2-naphthalen-2-ylmorpholine
CAS Number
PubChem CID
Chemical and physical data
FormulaC15H17NO
Molar mass227.307 g·mol−1
3D model (JSmol)
  • CC1C(OCCN1)C2=CC3=CC=CC=C3C=C2
  • InChI=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
  • Key:SYFNRUAPFPQZQA-UHFFFAOYSA-N

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. It is an 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 EC50Tooltip half-maximal effective concentration values for induction of monoamine release are 111 nM for dopamine, 203 nM for norepinephrine, and inactive for serotonin in rat brain synaptosomes, whereas its IC50Tooltip half-maximal inhibitory concentration for serotonin reuptake inhibition is 105 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. 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).

Monoamine release of naphthylmetrazine and related agents (EC50Tooltip Half maximal effective concentration, nM)
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Ref
d-Amphetamine 6.6–10.2 5.8–24.8 698–1,765
Naphthylaminopropane (NAP; PAL-287) 11.1 12.6 3.4
d-Methamphetamine 12.3–14.3 8.5–40.4 736–1,292
Methylnaphthylaminopropane (MNAP; PAL-1046) 34 10 13
l-Methcathinone 13.1 14.8 1,772
2-Naphthylmethcathinone (BMAPN; βk-MNAP) 94% at 10 μM 34 27
d-Ethylamphetamine 28.8 44.1 333.0
Ethylnaphthylaminopropane (ENAP; PAL-1045) 137 46 a 12 a
2-Phenylmorpholine (PAL-632) 79 86 20,260
Naphthylmorpholine (PAL-678) 88% at 10 μM 79% at 10 μM 92% at 10 μM
Phenmetrazine 29–50.4 70–131 7,765–>10,000
Naphthylmetrazine (PAL-704) 203 111 RI (105)
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Footnotes: a ENAPTooltip Ethylnaphthylaminopropane is a partial releaser of serotonin (EmaxTooltip maximal efficacy = 66%) and dopamine (Emax = 78%). Refs:
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