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| Other names | ENAP;N-Ethylnaphthylaminopropane;N-Ethyl-NAP; PAL-1045; Ethamnetamine; Ethylnaphetamine; ENA; ENT;N-Ethylnaphthylisopropylamine; ENIPA |
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| Chemical and physical data | |
| Formula | C15H19N |
| Molar mass | 213.324 g·mol−1 |
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Ethylnaphthylaminopropane (ENAP; developmental code namePAL-1045) is amonoamine releasing agent (MRA) of theamphetamine andnaphthylaminopropane families that is related tonaphthylaminopropane (NAP; PAL-287) andmethamnetamine (MNAP; PAL-1046).[1][2][3] It acts specifically as aserotonin–norepinephrine–dopamine releasing agent (SNDRA).[2][3] However, ENAP is unusual in being apartial releaser ofserotonin anddopamine and a full releaser ofnorepinephrine.[1][2][3]
TheEC50Tooltip half-maximal effective concentration (EmaxTooltip maximal efficacy) values of ENAP in terms of monoamine release induction are 12 nM (66%) for serotonin, 46 nM (78%) for dopamine, and 137 nM (94%) for norepinephrine in rat brainsynaptosomes.[2][3] In contrast to NAP and MNAP, which produce clearlydose-dependent increases inlocomotor stimulation and brain monoamine levels in rodents, ENAP has been found to show attenuated monoamine elevations and a "flat"dose–response curve.[4][3] Relatedly, it may have lessmisuse liability than other drugs likeamphetamine, although more research is necessary to assess this possibility.[4][3]
In addition to its MRA activity, ENAP has been found to be an effectivepharmacological chaperone for rescuingmisfoldedmutantmonoamine transporters (MATs).[5][6]
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref |
|---|---|---|---|---|
| d-Amphetamine | 6.6–10.2 | 5.8–24.8 | 698–1,765 | [7][8][9][10][11] |
| Naphthylaminopropane (NAP; PAL-287) | 11.1 | 12.6 | 3.4 | [12][9] |
| d-Methamphetamine | 12.3–14.3 | 8.5–40.4 | 736–1,292 | [7][13][9][11] |
| Methylnaphthylaminopropane (MNAP; PAL-1046) | 34 | 10 | 13 | [3][2] |
| l-Methcathinone | 13.1 | 14.8 | 1,772 | [14][10] |
| 2-Naphthylmethcathinone (BMAPN; βk-MNAP) | 94% at 10 μM | 34 | 27 | [15][16] |
| d-Ethylamphetamine | 28.8 | 44.1 | 333.0 | [17][18] |
| Ethylnaphthylaminopropane (ENAP; PAL-1045) | 137 | 46a | 12a | [3] |
| Phenmetrazine | 29–50.4 | 70–131 | 7,765–>10,000 | [19][9][20][21] |
| Naphthylmetrazine (PAL-704) | 203 | 111 | RI (105) | [21] |
| 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:a ENAP is apartial releaser of serotonin (EmaxTooltip maximal efficacy = 66%) and dopamine (Emax = 78%).Refs:[22][23] | ||||
Other anti-amphetamine agents in preclinical research are the "partial substrates" also called "partial releasers." In a large series of phenethylamine structures, Blough and colleagues (see Reith et al. 2015) observed that upon increasing size, substrate releaser activity converted to uptake inhibition; as the increasing size of the phenethylamine structure nears the edge of the pharmacophore, the releasing potency weakens even before the compound becomes an uptake inhibitor. It is in this structural border region where we find the partial releasers. Thus, PAL-1045 (N-ethyl-naphtylaminopropane or ENAP) and PAL-193 (3,4-methylenedioxy-Nethylamphetamine), rather than being substrates with full releasing capability, released no more than 78% and 61%, respectively, of preloaded [3 H]MPP+ from rat synaptosomes (Rothman et al. 2012; Reith et al. 2015). PAL-1045, as bupropion, stabilizes inward conformations of monoamine transporters but, unlike bupropion, is still a substrate (Bhat et al. 2017 and see below final paragraph of this section). Whereas the full releaser 2-naphthyl analog of amphetamine, NAP, dosedependently increased accumbal dialysate DA, PAL-1045 showed a low-efficacy flat dose-response curve (Rothman et al. 2012) in accordance with its partial releasing character.
Another line of evidence for the selective modulation of reverse transport comes from our recent report that different DAT substrates can have variable efficacies for inducing DAT-mediated efflux of the labeled substrate [3H]MPP+. For example, whereas the full substrate naphthylaminopropane (NAP, the (2-naphthyl)-analog of amphetamine, also known as PAL-278; see Fig. 2A for structure) produced complete efflux of preloaded [3H]MPP+ from rat synaptosomes within 30 minutes (Emax, ∼100%), N-ethyl-naphthylaminopropane (ENAP, also known as PAL-1045; Fig. 2B) was unable to elicit complete [3H]MPP+ release within the experimental period (efflux reached a plateau, with Emax = 78%). Similarly, although the empathogen 3,4-methylenedioxyamphetamine is a full DAT substrate (Rothman et al., 2009), the ethyl analog 3,4-methylenedioxy-N-ethylamphetamine behaved as a partial substrate, with an Emax value of roughly 65%. Of importance, the plateau in transporter-mediated [3H]MPP+ efflux was insurmountable; merely increasing the concentration of a partial substrate did not produce complete release. In addition, the attenuated response observed for partial substrates in [3H]MPP+ release assays was also demonstrated in vivo: whereas NAP produced clear dose-dependent increases in locomotor stimulation and extraneuronal DA levels in rats, ENAP showed a flat dose-response curve (Rothman et al., 2012). However, the question of whether the attenuated monoamine-releasing effect of partial substrates, such as ENAP, is genuinely consequential in vivo will require further tests of such compounds in relevant behavioral assays, such as self-administration, drug discrimination, and conditioned place preference.
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. [...]