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| Formula | C16H23NO2 |
| Molar mass | 261.365 g·mol−1 |
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Etoxadrol (CL-1848C) is adissociativeanaesthetic drug that has been found to be anNMDA antagonist and produce similar effects toPCP in animals.[1][2] Etoxadrol, along with another related drugdexoxadrol, were developed asanalgesics for use in humans, but development was discontinued in the late 1970s after patients reported side effects such asnightmares andhallucinations.[3][4][5]
Phencyclidine (PCP),tenocyclidine (TCP), etoxadrol and its precursor,dexoxadrol have related chemical structures.[6] These drugs all act similarly on thenervous system, acting asdissociativehallucinogens (meaning that they interfere with normal sensory signals, replacing them withhallucinations of any sensory modality!) withanesthetic andanalgesic properties.
Etoxadrol is anon-competitiveNMDA receptor antagonist.[7] It binds with highaffinity to thePCPbinding site on theNMDA receptor (Ki = 107 nM, determined by the displacement ofradiolabeledTCP).[1][3] Normally, the inactivatedNMDA receptor possesses amagnesium (Mg2+) block in thechannel, blocking the passage ofcations.[8]
When theneurotransmitterglutamate binds to theNMDA receptor, and thepostsynapticcell membrane isdepolarized (from the postsynaptic cell being activated), themagnesium block in theNMDA receptor channel is displaced.Calcium (Ca2+) andsodium (Na+) can enter thecell via the open channel, whilepotassium (K+) can exit the cell. Etoxadrolantagonizes theNMDA receptor by binding to thePCP site, located just above themagnesium block in theion channel. In the event that themagnesium block is displaced, etoxadrol blocks theNMDA receptor channel, preventingcations from entering or exiting the channel. This mechanism of action also applies toPCP,TCP,ketamine anddexoxadrol.
Etoxadrol binding does not affect thebinding affinity of other sites on theNMDA receptor, as found by binding studies showing the displacement ofradiolabeledTCP by etoxadrol (TCP binding in the absence of etoxadrol:Ki = 19.2 x 10−9 M, Bmax = 1.36 pmol/mgprotein; TCP binding in the presence of etoxadrol: Ki = 21.7 x 10−9 M, Bmax = .66 pmol/mg protein).[9]
Despite itsanesthetic andanalgesic effects, etoxadrol does not interact withbenzodiazepine,muscarinic acetylcholine, ormu opioid receptors.[9] However, etoxadrol may act in thedopaminereward pathway, explaining itsreinforcing properties.[6]
Etoxadrol goes into effect 90 seconds afterintravenous (IV) administration, and itsanesthetic effects typically last for half an hour to an hour.[5][10] Since etoxadrol is administered intravenously, thebioavailable dose is always the same as the administered dose. Etoxadrol'sanalgesic effects can last for up to 2 hours or more after patients have regainedconsciousness.[11]
Etoxadrol islipophilic and can readily cross theblood–brain barrier. Because of itslipophilic structure, etoxadrol can be absorbed byfat tissues andorgans (e.g. theliver). Etoxadrol also acts on therespiratory andcardiovascular systems.[10]
Etoxadrol was intended as ananesthetic for patients requiring particularly long periods ofanesthesia forsurgery. As ananesthetic, etoxadrol is morepotent thanketamine, but less potent thanPCP.[11]
Etoxadrol is also a potentanalgesic. Patients given etoxadrol often reported that they were aware of experiencingpain upon waking fromanesthesia, but it did not bother them.[5] Post-operative analgesics are rarely required after patients undergoingsurgery are administered etoxadrol.
Etoxadrol (along withketamine,dexoxadrol, and otherPCP-like drugs) is ananticonvulsant, preventingtonic seizures inmice that are administeredpentylenetetrazol (PTZ), which normally inducesseizures.[12]
Likeketamine, etoxadrol produces increases inheart rate andrespiratory rate.[10] Etoxadrol may also causevomiting.[5] At high enoughdoses, etoxadrol also exhibits effects on themuscular system such asconvulsions or loss of therighting reflex.[13] When administered in excess, etoxadrol can belethal on therespiratory system.Monkeys given extremely high (> 20 mg/kg)doses of etoxadrol died of apparentrespiratory failure.
Etoxadrol produces a wide variety ofdreams, ranging from pleasant to frightening or aversive.[11] Approximately half of patients given etoxadrol report pleasant dreams, 25% report unpleasant dreams, and the remaining 25% experience no dreams at all. Such dreams were frequently described as “floating,” “puffy” or “out of this world." Dreams andhallucinations may persist for as long as 18 to 24 hours. In rare cases, etoxadrol can induce periods ofpsychotic activity during this recovery period.[5]
In thebrain, etoxadrol slows down thesynthesis ofserotonin to 50-60% of control rates and speeds up the rate ofdopamine synthesis by up to 200% of the normal rate 4–6 hours afterintravenous administration.[5]
Like a number of otherdrugs (e.g.cocaine), etoxadrol has been found to exhibitreinforcing properties.Monkeys will self-administer etoxadrol,dexoxadrol orPCP in a lever-pressing paradigm.[6]
