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Ethylnaphthylaminopropane

Clinical data
Other names	ENAP; N-Ethylnaphthylaminopropane; N-Ethyl-NAP; PAL-1045; Ethamnetamine; Ethylnaphetamine; ENA; ENT; N-Ethylnaphthylisopropylamine; ENIPA
Identifiers
IUPAC name N-ethyl-1-naphthalen-2-ylpropan-2-amine
PubChem CID	61080203
ChemSpider	38754192
Chemical and physical data
Formula	C15H19N
Molar mass	213.324 g·mol
3D model (JSmol)	Interactive image
SMILES CCNC(C)CC1=CC2=CC=CC=C2C=C1
InChI InChI=1S/C15H19N/c1-3-16-12(2)10-13-8-9-14-6-4-5-7-15(14)11-13/h4-9,11-12,16H,3,10H2,1-2H3 Key:HKSRURFPXCLKOG-UHFFFAOYSA-N

Ethylnaphthylaminopropane (ENAP; developmental code name PAL-1045) is a monoamine releasing agent (MRA) of the amphetamine family that is related to naphthylaminopropane (NAP; PAL-287) and methamnetamine (MNAP; PAL-1046). It acts specifically as a serotonin–norepinephrine–dopamine releasing agent (SNDRA). However, ENAP is unusual in being a partial releaser of serotonin and dopamine and a full releaser of norepinephrine.

The EC₅₀Tooltip half-maximal effective concentration (E_maxTooltip 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 brain synaptosomes. In contrast to NAP and MNAP, which produce clearly dose-dependent increases in locomotor stimulation and brain monoamine levels in rodents, ENAP has been found to show attenuated monoamine elevations and a "flat" dose–response curve. Relatedly, it may have less misuse liability than other drugs like amphetamine, although more research is necessary to assess this possibility.

In addition to its MRA activity, ENAP has been found to be an effective pharmacological chaperone for rescuing misfolded mutant monoamine transporters (MATs).

References

1. ^ Reith ME, Gnegy ME (2020). "Molecular Mechanisms of Amphetamines". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 258: 265–297. doi:10.1007/164_2019_251. ISBN 978-3-030-33678-3. PMID 31286212. 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 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.
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4. ^ Schmitt KC, Rothman RB, Reith ME (July 2013). "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". J Pharmacol Exp Ther. 346 (1): 2–10. doi:10.1124/jpet.111.191056. PMC 3684841. PMID 23568856. 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 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 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 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 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 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.
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