Etoxadrol
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| Formula | C16H23NO2 |
| Molar mass | 261.365 g·mol−1 |
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Etoxadrol (CL-1848C) is a dissociative anaesthetic drug that has been found to be an NMDA antagonist and produce similar effects to PCP in animals.[1][2] Etoxadrol, along with another related drug dexoxadrol, were developed as analgesics for use in humans, but development was discontinued in the late 1970s after patients reported side effects such as nightmares and hallucinations.[3][4][5]
Phencyclidine (PCP), tenocyclidine (TCP), etoxadrol and its precursor, dexoxadrol have related chemical structures.[6] These drugs all act similarly on the nervous system, acting as dissociative hallucinogens (meaning that they interfere with normal sensory signals, replacing them with hallucinations of any sensory modality!) with anesthetic and analgesic properties.
Pharmacodynamics
Etoxadrol is a non-competitive NMDA receptor antagonist.[7] It binds with high affinity to the PCP binding site on the NMDA receptor (Ki = 107 nM, determined by the displacement of radiolabeled TCP).[1][3] Normally, the inactivated NMDA receptor possesses a magnesium (Mg2+) block in the channel, blocking the passage of cations.[8]
When the neurotransmitter glutamate binds to the NMDA receptor, and the postsynaptic cell membrane is depolarized (from the postsynaptic cell being activated), the magnesium block in the NMDA receptor channel is displaced. Calcium (Ca2+) and sodium (Na+) can enter the cell via the open channel, while potassium (K+) can exit the cell. Etoxadrol antagonizes the NMDA receptor by binding to the PCP site, located just above the magnesium block in the ion channel. In the event that the magnesium block is displaced, etoxadrol blocks the NMDA receptor channel, preventing cations from entering or exiting the channel. This mechanism of action also applies to PCP, TCP, ketamine and dexoxadrol.
Etoxadrol binding does not affect the binding affinity of other sites on the NMDA receptor, as found by binding studies showing the displacement of radiolabeled TCP by etoxadrol (TCP binding in the absence of etoxadrol: Ki = 19.2 × 10−9 M, Bmax = 1.36 pmol/mg protein; TCP binding in the presence of etoxadrol: Ki = 21.7 × 10−9 M, Bmax = .66 pmol/mg protein).[9]
Despite its anesthetic and analgesic effects, etoxadrol does not interact with benzodiazepine, muscarinic acetylcholine, or mu opioid receptors.[9] However, etoxadrol may act in the dopamine reward pathway, explaining its reinforcing properties.[6]
Pharmacokinetics
Etoxadrol goes into effect 90 seconds after intravenous (IV) administration, and its anesthetic effects typically last for half an hour to an hour.[5][10] Since etoxadrol is administered intravenously, the bioavailable dose is always the same as the administered dose. Etoxadrol's analgesic effects can last for up to 2 hours or more after patients have regained consciousness.[11]
Etoxadrol is lipophilic and can readily cross the blood–brain barrier. Because of its lipophilic structure, etoxadrol can be absorbed by fat tissues and organs (e.g. the liver). Etoxadrol also acts on the respiratory and cardiovascular systems.[10]