Ketamine, structure

Psychotomimetic Drugs. Figure 2 Chemical structures of the dissociative anesthetics phencyclidine (PCP) and ketamine. Both are arylcycloalkylamine derivatives that are open channel blockers of the NMDA channel. 

This laboratory has utilized two approaches to define further the anticonvulsant properties of PCP. One approach involved a relatively simple convulsant model, pentylenetetrazol-induced convulsions. In this model, the administration of ketamine alone, or in combination with several known anticonvulsants, was tested. Ketamine, as a structural analog of PCP, shares many of the pharmacological properties associated with PCP. The second approach involved a more complex model, hippocampal-kindled seizures. 

Generalization tests indicated that a number of compounds were able to substitute for PCP (table 1). Ketamine and tiletamine, which are structurally similar to PCP, produced dose-dependent effects mimicking PCP. These compounds are interesting examples of the structural requirements of molecules for PCP-mimetic activity, demonstrating that neither the piperidine nor the phenyl moieties are absolutely necessary for activity. 

The chemical structure of ketamine is similar to that of the potent psychedelic PCP (Figure 6.2). Not surprisingly, ketamine produces many psychedelic effects that are similar to those produced by PCP. However, ketamine s effects are much shorter in duration—a trip on ketamine may last only 30-60 minutes, whereas a trip on PCP may last several hours. The onset of ketamine s actions is quite rapid (i.e., within minutes), especially if snorted or injected intravenously. 

Figure 6.2 The chemical structure of ketamine (top) is related to the psychedelic PCP (bottom). Both chemicals produce strong hallucinations and psychedelic effects. However, while the effects of ketamine may only last an hour, the effects of PCP can last several hours after the drug is taken.

Ketamine and also tiletamine are structurally and pharmacologically related to phencyclidine. Its mechanism of action is not well understood. It has been suggested that it blocks the membrane effects of the excitatory neurotransmitter glutamic acid. Ketamine produces dissociative anesthesia, which means that the patient seems to be awake but there are no responses to sensory stimuli. Ketamine, which can be administered IV or IM, has strong analgesic activity. It is especially indicated for interventions of short duration without any need for skeletal... 

Figure 4.4 Structural formulae of propofol, etomidate, and ketamine.

A putative back-up of this structural class might be AR-R-15,896 which is at least in preclinical development by AstraZeneca (company communication). Compared to ketamine and memantine, AR-R-15,896 might have more favorable pharmacodynamic features (Mealing et al.,... 

Phencyclidine, PCP, or l-(l-phenylcyclohexyl) piperidine, is an arylcyclohexamine with structural similarities to ketamine. It is a lipophilic weak base with a pKa of 8.5. Phencyclidine was originally synthesized and marketed under the trade name Semyl by Parke-Davis for use as an intravenously administered anesthetic agent in humans. Distribution began in 1963 but was discontinued in 1965 due to a high incidence (10 to 20%) of post-operative delirium and psychoses. However, its use continued as a veterinary tranquilizer for large animals until 1978, when all manufacture was prohibited and PCP was placed in Schedule II of the federal Controlled Substances Act (1970). 

Ketamine, a weakly basic compound structurally and pharmacologically similar to phencyclidine, is utilized in the U.S. to induce anesthesia.1 It is available in solution for intravenous or intramuscular injection. Since the drug is pharmacologically similar to PCP it has the potential of producing hallucinogenic effects and, therefore, in recent years has become a drug of abuse. 

Another member of the arylcyclohexylamine structural class is ketamine, which is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, meaning it disables certain higher-function signaling mechanisms in the brain (consciousness, memory, perception, and motor activity) from lower functions (breathing and heart rate). Ketamine is manufactured commercially for use as a surgical anesthetic for both humans and animals. 

Several drugs are used intravenously, alone or in combination with other drugs, to achieve an anesthetic state (as components of balanced anesthesia) or to sedate patients in intensive care units who must be mechanically ventilated. These drugs include the following (1) barbiturates (thiopental, methohexital) (2) benzodiazepines (midazolam, diazepam) (3) opioid analgesics (morphine, fentanyl, sufentanil, alfentanil, remifentanil) (4) propofol (5) ketamine and (6) miscellaneous drugs (droperidol, etomidate, dexmedetomidine). Figure 25-2 shows the structures of... 

Phencyclidine has been favoured as an illicit drug of abuse for some 20 years, but such a use appears to have declined recently owing to the availability of relatively inexpensive cocaine. The drug has the street names of "PCP", "angel dust and "crystal". The structures of phencyclidine and ketamine are shown in Figure 15.7. 

Figure 15.7. Structures of the psychotomimetic compound phencyclidine and the structurally related dissociative anaesthetic ketamine.

The title complex represents the parent compound of several known metalla-/3-iminoketone molecules.2 In each case a metalla-/3-diketone molecule is treated with a primary amine, affording the corresponding metalla-/3-imino-ketone derivative. The structure of the cis-tetracarbonylrhenium metalla analogue of N-phenylacetimidoylacetone has been determined.3 The structure of this complex confirms the formulation of these complexes as metalla analogues of the ketamine tautomer of /3-iminoketone molecules. However, the electronic structure is described best by the zwitterionic resonance form shown below. 

Ketamine is a compound with a molecular structure similar to that of phencyclidine (Figure 4.2). The pharmaceutical versions of ketamine are clear, colorless liquids available in varying concentrations of 10,50, and 100 milligram/milliliter solutions (Figure 4.3). Many recreational users inject this liquid intramuscularly or intravenously. It is the liquid formulation that is used as a date rape drug. Liquid ketamine, which is clear and colorless, can easily be slipped into a drink without being detected. 

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