Etoxadrol (CL-1848C) is a

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

anaesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...

drug that has been found to be an

NMDA antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...

and produce similar effects to PCP in animals. 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 A nightmare, also known as a bad dream, Retrieved 11 July 2016. is an unpleasant dream that can cause a strong emotional response from the mind, typically fear but also despair, anxiety or great sadness. The dream may contain situations of d ...

and hallucinations.

Chemical structure

Phenicyclidine (PCP), tenocyclidine (TCP), etoxadrol and its precursor, dexoxadrol have related chemical structures. These drugs all act similarly on the

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...

, acting as

hallucinogen Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorize ...

s (meaning that they interfere with normal sensory signals, replacing them with

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...

s of any sensory modality) with

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...

and analgesic properties.

Pharmacodynamics

Etoxadrol is a non-competitive

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...

. It binds with high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

to the PCP

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

on the NMDA receptor ( K_i = 107 nM, determined by the displacement of

radiolabeled A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by tr ...

TCP). Normally, the inactivated NMDA receptor possesses a magnesium (Mg²⁺) block in the channel, blocking the passage of

cations An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by con ...

When the neurotransmitter glutamate binds to the NMDA receptor, and the

postsynaptic Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

is depolarized (from the postsynaptic cell being activated), the

magnesium Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ta ...

block in the NMDA receptor channel is displaced. Calcium (Ca²⁺) and sodium (Na⁺) can enter the

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

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

block in the ion channel. In the event that the

block is displaced, etoxadrol blocks the NMDA receptor channel, preventing

from entering or exiting the channel. This mechanism of action also applies to PCP, TCP,

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...

and dexoxadrol. Etoxadrol binding does not affect the

binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...

of other sites on the NMDA receptor, as found by binding studies showing the displacement of

TCP by etoxadrol (TCP binding in the absence of etoxadrol: K_i = 19.2 x 10⁻⁹ M, B_max = 1.36 pmol/mg

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

; TCP binding in the presence of etoxadrol: K_i = 21.7 x 10⁻⁹ M, B_max = .66 pmol/mg protein). Despite its

and analgesic effects, etoxadrol does not interact with benzodiazepine, muscarinic acetylcholine, or mu opioid receptors. However, etoxadrol may act in the dopamine

reward pathway The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventra ...

, explaining its reinforcing properties.

Pharmacokinetics

Etoxadrol goes into effect 90 seconds after intravenous (IV) administration, and its

effects typically last for half an hour to an hour. 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 Consciousness, at its simplest, is sentience and awareness of internal and external existence. However, the lack of definitions has led to millennia of analyses, explanations and debates by philosophers, theologians, linguisticians, and scien ...

. Etoxadrol is

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

and can readily cross the blood–brain barrier. Because of its

structure, etoxadrol can be absorbed by fat tissues and

organs In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a f ...

(e.g. the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

). Etoxadrol also acts on the

respiratory The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies gre ...

and cardiovascular systems.

Treatment

Etoxadrol was intended as an

for patients requiring particularly long periods of anesthesia for surgery. As an

, etoxadrol is more potent than

, but less potent than PCP. Etoxadrol is also a potent analgesic. Patients given etoxadrol often reported that they were aware of experiencing pain upon waking from anesthesia, but it did not bother them. Post-operative analgesics are rarely required after patients undergoing surgery are administered etoxadrol. Etoxadrol (along with

, dexoxadrol, and other PCP-like drugs) is an anticonvulsant, preventing tonic seizures in mice that are administered pentylenetetrazol (PTZ), which normally induces

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

Side effects

, etoxadrol produces increases in

heart rate Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and excr ...

and

respiratory rate The respiratory rate is the rate at which breathing occurs; it is set and controlled by the respiratory center of the brain. A person's respiratory rate is usually measured in breaths per minute. Measurement The respiratory rate in humans is me ...

. Etoxadrol may also cause

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

. At high enough doses, etoxadrol also exhibits effects on the

muscular system The muscular system is an organ system consisting of skeletal, smooth, and cardiac muscle. It permits movement of the body, maintains posture, and circulates blood throughout the body. The muscular systems in vertebrates are controlled through t ...

such as

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...

or loss of the

righting reflex The righting reflex, also known as the labyrinthine righting reflex, is a reflex that corrects the orientation of the body when it is taken out of its normal upright position. It is initiated by the vestibular system, which detects that the body is ...

. When administered in excess, etoxadrol can be

lethal Lethality (also called deadliness or perniciousness) is how capable something is of causing death. Most often it is used when referring to diseases, chemical weapons, biological weapons, or their toxic chemical components. The use of this ter ...

on the

respiratory system The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies ...

. Monkeys given extremely high (> 20 mg/kg) doses of etoxadrol died of apparent

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...

. Etoxadrol produces a wide variety of

dreams A dream is a succession of images, ideas, emotions, and sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around 5 to 20 minutes, althou ...

, ranging from pleasant to frightening or aversive. 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 and hallucinations may persist for as long as 18 to 24 hours. In rare cases, etoxadrol can induce periods of psychotic activity during this recovery period. In the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

, etoxadrol slows down the synthesis of serotonin to 50-60% of control rates and speeds up the rate of dopamine synthesis by up to 200% of the normal rate 4–6 hours after intravenous administration. Like a number of other drugs (e.g.

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

), etoxadrol has been found to exhibit reinforcing properties. Monkeys will self-administer etoxadrol, dexoxadrol or PCP in a lever-pressing paradigm.

References

{{Ionotropic glutamate receptor modulators Dioxolanes Dissociative drugs Abandoned drugs 2-Piperidinyl compounds