Ketamine Hydrochloride: Structure,Synthesis,SAR,Mechanism,Uses

Ketamine Hydrochloride

Structure –

Here is the chemical structure of Ketamine Hydrochloride:

Ketamine Hydrochloride

Ketamine Hydrochloride is a salt of the compound ketamine, which is a medication used for anesthesia and pain relief. The structure shown here represents the molecular structure of the ketamine molecule with a hydrochloride ion (Cl-) added to it.

Synthesis –

Ketamine Hydrochloride can be synthesized in several steps, starting from the precursor compound 2-chlorobenzonitrile. Here is a simplified synthesis of Ketamine Hydrochloride:

  1. Conversion of 2-chlorobenzonitrile to 2-chloro-2′-hydroxydiphenylmethane: The first step involves the reaction of 2-chlorobenzonitrile with benzyl magnesium chloride in the presence of a palladium catalyst to form 2-chloro-2′-benzyloxydiphenylmethane. This intermediate is then treated with sodium hydroxide to remove the benzyl protecting group, yielding 2-chloro-2′-hydroxydiphenylmethane.
  2. Conversion of 2-chloro-2′-hydroxydiphenylmethane to ketamine: In the second step, 2-chloro-2′-hydroxydiphenylmethane is reacted with cyclopentylmagnesium bromide to form 2-chloro-2′-hydroxycyclohexyl-2-phenylethanone. This intermediate is then reacted with methylamine in the presence of hydrogen gas and a nickel catalyst to yield ketamine.
  3. Formation of Ketamine Hydrochloride: Finally, Ketamine is converted to its hydrochloride salt by adding hydrochloric acid to the solution of Ketamine in a suitable solvent.

Here is the simplified chemical equation for the synthesis of Ketamine Hydrochloride:

2-chlorobenzonitrile + benzyl magnesium chloride + Pd catalyst → 2-chloro-2′-benzyloxydiphenylmethane 2-chloro-2′-benzyloxydiphenylmethane + NaOH → 2-chloro-2′-hydroxydiphenylmethane 2-chloro-2′-hydroxydiphenylmethane + cyclopentylmagnesium bromide → 2-chloro-2′-hydroxycyclohexyl-2-phenylethanone 2-chloro-2′-hydroxycyclohexyl-2-phenylethanone + methylamine + H2 + Ni catalyst → Ketamine Ketamine + HCl → Ketamine Hydrochloride

SAR –

The SAR (Structure-Activity Relationship) of Ketamine Hydrochloride is complex and not fully understood, as its mechanism of action involves interactions with multiple receptors and neurotransmitter systems in the brain. However, some key features of the molecule that are thought to be important for its activity include:

  1. The arylcyclohexylamine structure: Ketamine belongs to the arylcyclohexylamine class of compounds, which also includes phencyclidine (PCP) and related drugs. This structure is thought to be important for its interaction with the NMDA receptor and other receptors in the brain.
  2. The presence of both an amine and a carbonyl group: Ketamine has both an amine group and a carbonyl group, which are thought to be important for its interaction with the NMDA receptor. The amine group can form hydrogen bonds with the receptor, while the carbonyl group can interact with the receptor through pi-stacking and electrostatic interactions.
  3. The presence of a chiral center: Ketamine is a chiral molecule, meaning that it exists in two enantiomeric forms (R and S). Studies have shown that the S-enantiomer is more potent than the R-enantiomer for some of Ketamine’s effects, including anesthesia and analgesia.
  4. The presence of the hydrochloride salt: Ketamine Hydrochloride is a salt of Ketamine, in which the hydrochloride ion (Cl-) is added to the molecule. This salt form is important for its solubility and stability, as well as for its use in medical applications.

Overall, the SAR of Ketamine Hydrochloride is complex and involves multiple features of the molecule, including its structure, stereochemistry, and salt form.

Mechanism –

The exact mechanism of action of Ketamine Hydrochloride is not fully understood, but it is believed to work through a variety of mechanisms involving interactions with several neurotransmitter systems in the brain.

Ketamine is an antagonist of the NMDA (N-methyl-D-aspartate) receptor, which is a type of glutamate receptor. By blocking the NMDA receptor, Ketamine reduces the activity of glutamate, which is an excitatory neurotransmitter in the brain. This results in decreased neural activity, leading to the anesthetic and analgesic effects of Ketamine.

Ketamine also has activity at several other receptor types, including opioid receptors, muscarinic receptors, and monoamine transporters. It can increase the release of dopamine, serotonin, and norepinephrine in the brain, leading to some of its psychoactive effects.

Additionally, Ketamine has been found to increase the activity of certain types of GABA (gamma-aminobutyric acid) receptors, which are inhibitory neurotransmitter receptors in the brain. This may contribute to the sedative and anxiolytic effects of Ketamine.

Overall, the precise mechanism of Ketamine Hydrochloride’s action is complex and multifaceted, involving interactions with multiple neurotransmitter systems in the brain.

Uses –

Ketamine Hydrochloride has several medical uses, including:

  1. Anesthesia: Ketamine Hydrochloride is used as a general anesthetic for both humans and animals. It is particularly useful in situations where traditional anesthetics may not be safe, such as in patients with compromised cardiac or respiratory function.
  2. Analgesia: Ketamine Hydrochloride is also used as an analgesic (pain reliever) in a variety of settings, including acute pain, chronic pain, and cancer pain. It has been shown to be particularly effective in treating neuropathic pain and pain associated with complex regional pain syndrome.
  3. Sedation: Ketamine Hydrochloride is sometimes used for procedural sedation, particularly in emergency settings or for patients who are difficult to sedate with traditional sedatives.
  4. Treatment of depression and other psychiatric disorders: Ketamine Hydrochloride has gained attention in recent years for its potential as a treatment for depression and other psychiatric disorders, such as post-traumatic stress disorder (PTSD) and anxiety disorders. It is believed to work by increasing synaptic plasticity and promoting the growth of new neural connections in the brain.
  5. Veterinary medicine: Ketamine Hydrochloride is commonly used as a veterinary anesthetic, particularly in small animals and exotic species.

It is important to note that Ketamine Hydrochloride can have significant side effects, particularly at higher doses, and should only be used under the supervision of a qualified healthcare provider.

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