N-Ethylhexedrone (also known as α-ethylaminohexiophenone, α-EAHP, α-ethylamino-caprophenone, N-ethylnorhexedrone, Ethylnorhexedrone, Norhexedrone, Ethylhexedrone, hexen, and NEH) is a stimulant of the cathinone class that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) with IC50 inhibition values of 0.0978 and 0.0467 μM, respectively (97 nM and 46 nM). N-Ethylhexedrone was first mentioned in a series of patents by Boehringer Ingelheim in the 1960s which led to the development of the better-known drug methylenedioxypyrovalerone (MDPV). Since the mid-2010s, N-ethylhexedrone has been sold online as a designer drug. In 2018, N-ethylhexedrone was the second most common drug of the cathinone class to be identified in Drug Enforcement Administration seizures. N-Ethylhexedrone was first synthesized by Boehringer Ingelheim in 1964. It appears to have emerged on the online research chemical market in late 2015. It is an example of a novel psychoactive substance specifically chosen to mimic the features of prohibited substances and bypass drug laws. It is one of a number of substances collectively referred to as "bath salts". User reports characterize N-ethylhexedrone as having euphoric stimulant effects comparable to those of crack cocaine and α-PVP-type compounds, particularly when they are insufflated or vaporized. Like other substituted cathinones, N-ethylhexedrone has gained notoriety for its association with compulsive redosing and addictive behaviors when abused.
History and culture N-Ethylhexedrone was patented by the German pharmaceutical company Boehringer Ingelheim in 1964 as a potential anorexigenic agent. The patent describes its synthesis together with other derivatives of aminoketone. The substance spread remarkably quickly in the NPS market in different European countries. It was first identified in a sample from the Belgian Customs laboratory which was received at the JRC in November 2015. In January 2016, it was identified at the JRC in a sample provided by French Customs. Subsequently, in February 2016, the EMCDDA received notifications of the identification of this substance from other countries, such as Sweden, The Netherlands, France, Belgium and Slovenia. In 2017 it was the most frequent seized cathinone in the EU, Norway and Turkey. In 2018, it was the most commonly identified cathinone after pentylone in Drug Enforcement Administration seizures.
Chemistry N-Ethylhexedrone is a derivative of hexedrone, in which the methyl group attached to the nitrogen atom is substituted by an ethyl group. It is structurally similar to pentedrone, and also α-pyrrolidinohexiophenone (A-PHP), from which it differs by the substitution of a pyrrolidine group with an N-ethyl group. The compound is a molecule of the cathinone chemical class. The term "substituted cathinone" refers to a broad array of substances based on cathinone, the principally active constituent of the khat plant. Cathinone is principally constituted of a amphetamine core (a phenethylamine core with an alkyl group attached to the alpha carbon) and an oxygen group attached to the beta carbon. Cathinones are also known as the beta-ketone (βk) (double-bonded oxygen to the β-carbon) analogs of amphetamines. Notably, the cathinone backbone can be modified in three different places to create hundreds of possible compounds, which include substituents on the aromatic ring (R2-R5), the alpha carbon (Rα), or the amine group (RN1, RN2). Relative to cathinone, N-ethylhexedrone consists of two added substitutions. At the Rα position, a n-butyl substitution forms a hexan chain. The second substitution is an ethyl group, that's attached to the amine group at RN2, thus forming N-ethyl.
Pharmacology
Very little data exists on the human pharmacokinetics and pharmacodynamics of N-ethylhexedrone and many other recently introduced substituted cathinones, aside from post-mortem results in overdose cases. Like amphetamines, synthetic cathinones exert their stimulating and sympathomimetic effects via increasing synaptic concentration of catecholamines such as dopamine, serotonin and norepinephrine. These molecules are able to inhibit monoamine reuptake transporters producing a decreased clearance of the neurotransmitters from the synapse. Furthermore, they may cause release of biogenic amines from intracellular stores. It appears that N-ethylhexedrone has high preference for the dopamine transporter. Based on the structure and assuming that N-ethylhexedrone is metabolized similarly to other cathinones, this compound is likely metabolized through N-dealkylation and/or reduction of the carbonyl group followed by N-dealkylation. Synthetic cathinones are generally less able than amphetamines to cross the blood–brain barrier because the beta-keto group causes an increase in polarity. Unlike other synthetic cathinones, pyrrolidine derivatives have a higher ability to cross the blood–brain barrier because the pyrrolidine ring confers a low polarity to these molecules. The studies on the metabolism of synthetic cathinones have shown that they are N-demethylated, the keto group is reduced to hydroxyl and ring alkyl groups are oxidised.
Legal status Internationally, N-ethylhexedrone was added to the UN Convention on Psychotropic Substances as a Schedule II controlled substance in March 2020.
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