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| Clinical data | |
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| Other names | PAL-704; PAL704; 3-Methyl-2-(2′-naphthyl)morpholine |
| Drug class | Norepinephrine–dopamine releasing agent;Serotonin reuptake inhibitor |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| Chemical and physical data | |
| Formula | C15H17NO |
| Molar mass | 227.307 g·mol−1 |
| 3D model (JSmol) | |
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Naphthylmetrazine (code namePAL-704), also known as3-methyl-2-(2′-naphthyl)morpholine, is amonoamine releasing agent (MRA) andmonoamine reuptake inhibitor (MRI) of thephenylmorpholine andnaphthylaminopropane families related tophenmetrazine.[1][2] It is ananalogue of phenmetrazine in which thephenyl ring has been replaced with anaphthalene ring.[1][2]
The drug acts as a hybridnorepinephrine–dopamine releasing agent (NDRA) andserotonin reuptake inhibitor (SRI).[1] ItsEC50Tooltip half-maximal effective concentration values for induction of monoamine release are 111 nM fordopamine, 203 nM fornorepinephrine, and inactive forserotonin in rat brainsynaptosomes, whereas itsIC50Tooltip half-maximal inhibitory concentration for serotonin reuptake inhibition is 105 nM.[1] Hence, it is aboutequipotent 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 ofchemical structure, naphthylmetrazine is to phenmetrazine[1][2] asnaphthylisopropylamine (PAL-287) is toamphetamine.[3][4] Other naphthylanalogues ofamphetamines and related compounds includemethamnetamine (PAL-1046; "naphthylmethamphetamine"),ethylnaphthylaminopropane (ENAP; PAL-1045; "naphthylethylamphetamine"),BMAPN (βk-methamnetamine; "naphthylmethcathinone"),methylnaphthidate (HDMP-28; "naphthylmethylphenidate"),ethylnaphthidate (HDEP-28; "naphthylethylphenidate"), andnaphyrone ("naphthyl-α-PVP" or "naphthylpyrovalerone"; O-2482).
A closely related compound to naphthylmetrazine isnaphthylmorpholine (PAL-678), the naphthyl analogue of the phenmetrazineparent compound2-phenylmorpholine (PAL-632).[1]
| 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 | 46a | 12a | [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. Theassays were done in rat brainsynaptosomes and humanpotencies may be different. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds.Footnotes:aENAPTooltip Ethylnaphthylaminopropane is apartial releaser of serotonin (EmaxTooltip maximal efficacy = 66%) and dopamine (Emax = 78%).Refs:[20][21] | ||||
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 [...]
RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.
FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]
