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= EG-2201 = EG-2201 [9-(5-fluoropentyl)-9H-carbazol-3-yl]-1-naphthalenyl-methanone is a synthetic cannabinoid that has emerged and was first seen on the new psychoactive substance market in Sweden on february 22, 2016. The substance has been shown to have a potent effect at both the CB1, and CB2 receptor: ‘EG-2201 (...) was investigated and found to induce agonistic behavior at both cannabinoid receptor subtypes. Its respective Ki and EC50 values were similar (CB1 Ki = 22.4 nM; EC50 = 15.6 nM; CB2 Ki = 4.36 nM and EC50 = 5.65 nM)’. As of today the substance seems to circumnavigate most countries' controlled substance and even analog acts by having a tweak in its backbone structure. The synthetic is marketed as a legal alternative to cannabis in the form of herbal mixtures or in its pure form as research chemical. Other synthetic cannabinoids include its analog AM-2201 and derivative EG-018. EG-2201 is a functional analog of Δ9-THC and anandamide by binding to cannabinoid receptors in the peripherical and central nervous system. The psychoactive cannabinoid plays a role in the regulation of feeding behaviour, and the neural generation of motivation and pleasure.

History
Synthetic cannabinoids have been under monitoring since their first detection in 2008. They were marketed online as legal alternatives to marijuana and usually sold as “research chemicals.” Most synthetic cannabinoids were built on an indole core until a patent application by Diaz et al. described a cannabinoid receptor modulator with a carbazole core. In June 2014 the first carbazole derived synthetic cannabinoid EG-018 was detected by Latvian police. EG-2201 is a newer development in the carbazole derived synthetic cannabinoids.

Chemical properties
EG-2201, (9-(5-fluoropentyl)-9H-carbazol-3-yl)(naphthalen-1-yl)methanone, is a room temperature solid, carbazole-derived synthetic cannabinoid. The molecule is created by Cayman Chemical as an analog to indazole AM-2201. EG-2201 consists of a carbazole group with carbonyl linker connected to a naphthyl residue and a benzene ring positioned adjacent to the aminoalkylindole group. The main psychoactive component, the heterocyclic scaffold, is lipophilic. Hence, it is an excellent substrate to cytochrome P450 enzymes and easily accumulates over body fat tissue. Its reactivity is similar to Δ9-THC in cannabis and binds therefore to the human CB1 receptor. EG-2201 ligands within three major places in the brain: the cerebellum, basal ganglia, and hippocampus. The chemical mimics the interaction between the endocannabinoid anandamide and the cannabinoid receptors. EG-2201 can only disrupt cell processes at receptor level and has therefore, as yet, no known chemical reactivity.

Pharmacology
The cannabinoid is a partial agonist for cannabinoid receptors CB1 and CB2. With a moderate selectivity and greater affinity for the human CB1 receptor, Ki of CB1 is 22.3 nM, and is 4.36 nM for the human CB2 receptor. However, the potency of EG-2201 is one of the lowest among synthetic cannabinoids. Unlike other synthetic cannabinoids, EG-2201 preferentially recruits the mini-Gα1 pathway over the β-arrestin2 to CB1. The substituted indole for carbazole in EG-2201 derives the preference for G protein-mediated coupling. Therefore, protein-ligand docking shows that EG-2201 interacts poorly with the orthosteric binding site pocket in the CB1-Gα1. The chemical lacks an oxygen group in the key position to establish a hydrogen bonding with water molecules and amide linker S3837.39 within the human CB1 receptor.

Mechanism of action
Ligand EG-2201 binds primarily to heterotrimer G protein-coupled receptor (GPCR) CB1, causing the protein to conformational change on the intracellular-side of the membrane. The conformation activates the replacement of GDP to GTP in the G protein alpha subunit. The G protein alpha subunit dissociates together with G beta-gamma from the GPCR and are able to interact with a variety of membrane proteins involved in signal transduction. The duration of active state of the G proteins is determined by the reassociation by hydrolysation of GTP in GDP in the alpha subunit. Both cannabinoid receptors exist of Gi/o protein linked GPCRs. The αi- and αo-subunit determine signal transduction after dissociation, namely the inhibition of voltage-gated calcium channels and adenylyl cyclase. Moreover, the dissociated α-subunit activates the inwardly-rectifying A-type potassium channels and MAP-kinase . CB1 and CB2 receptors are generally found in the central and peripheral nerve endings. These terminators have as function to enable chemical signalling, however the activated CB1 receptor inhibits the neurotransmitter release.

Absorption
The people who are most likely to be exposed to EG-2201 are NPS users. Exposure to the substance is thus likely to be a result of self administration. The substance is being sold as a powder, however similar substances in the past have been sold as mixtures of herbal material infused with the active substance. The route of administration may differ among users, and will most likely entail inhalation by vaporizing or burning the substance. There have not been any studies investigating the epithelial uptake of this substance, to get clear data on the uptake more work has to be done.

Distribution
There have not been any studies investigating the volume of distribution of this substance in animal models. The calculated octanol:water logP value of EG-2201 is 7.47. This lipophilicity entails that the molecule can be dispersed throughout the body and is likely to diffuse through membranes. This adds up positively to its potential volume of distribution. Secondly it has a molecular weight of 409.495 Da, which might make it a bit harder for the molecule to diffuse through the membranes out of the central circulation into the tissue cells. This will have a slight reducing effect on its volume of distribution in comparison to smaller xenobiotic molecules. In the environment of the human body the molecule will not be in an ionized state, this makes it less likely for the molecule to bind to plasma proteins, thus probably not further increasing its volume of distribution.

Metabolism
Up until this point most research on EG-2201 has been investigating its metabolism. For EG-2201, only one human urine sample of a known ingestion has been analyzed. In this sample seven metabolites were identified. The processes underlying the emergence of these metabolites are N-Dealkylation, hydroxylation, oxidative defluorination and combinations thereof . Furthermore several in vitro assays have been performed investigating potential metabolites of EG-2201, adding up to a total of 35 identified metabolites in seven categories.

Excretion
The final step in the toxicokinetics of a xenobiotic is its excretion from the body. As of today some research has been done on identifying potential targets for urinary drug screening. The current data points out the renal clearance of the seven metabolites found in the one urine sample that has been analyzed. The recommended targets for screening are its F1.1 & F1.2 metabolites, which are two structural isomers of EG-2201 which have been monohydroxilated at its pentyl chain.