Naphthylmetrazine

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.^[1][2] It is a analogue of phenmetrazine in which the phenyl ring has been replaced with a naphthalene ring.^[1][2]

Naphthylmetrazine

Clinical data
Other names	PAL-704; PAL704; 3-Methyl-2-(2′-naphthyl)morpholine
Drug class	Norepinephrine–dopamine releasing agent; Serotonin reuptake inhibitor
Identifiers
IUPAC name 3-methyl-2-naphthalen-2-ylmorpholine
CAS Number	1350769-57-1 Y
PubChem CID	54673725
Chemical and physical data
Formula	C15H17NO
Molar mass	227.307 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1C(OCCN1)C2=CC3=CC=CC=C3C=C2
InChI 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

The drug acts as a hybrid norepinephrine–dopamine releasing agent (NDRA) and serotonin reuptake inhibitor (SRI).^[1] 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.^[1] 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.^[1]

In terms of chemical structure, naphthylmetrazine is to phenmetrazine^[1][2] as naphthylisopropylamine (PAL-287) is to amphetamine.^[3][4] 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).^[1]

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	[5][6][7][8][9]
Naphthylaminopropane (NAP; PAL-287)	11.1	12.6	3.4	[4][7]
d-Methamphetamine	12.3–14.3	8.5–40.4	736–1,292	[5][10][7][9]
Methylnaphthylaminopropane (MNAP; PAL-1046)	34	10	13	[11][12]
l-Methcathinone	13.1	14.8	1,772	[13][8]
2-Naphthylmethcathinone (BMAPN; βk-MNAP)	94% at 10 μM	34	27	[14][15]
d-Ethylamphetamine	28.8	44.1	333.0	[16][17]
Ethylnaphthylaminopropane (ENAP; PAL-1045)	137	46 a	12 a	[11]
2-Phenylmorpholine (PAL-632)	79	86	20,260	[1]
Naphthylmorpholine (PAL-678)	88% at 10 μM	79% at 10 μM	92% at 10 μM	[1]
Phenmetrazine	29–50.4	70–131	7,765–>10,000	[18][7][19][1]
Naphthylmetrazine (PAL-704)	203	111	RI (105)	[1]
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: [20][21]