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Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.

The histamine H3 receptor is a Gi/o-coupled inhibitory autoreceptor primarily located on histaminergic nerve terminals, and is involved in modulating the release of histamine and other aminergic/peptidergic neurotransmitters in the brain. Drugs such as ciproxifan, which block the H3 receptor, lead to increased release of histamine and other excitatory neurotransmitters in the prefrontal cortex, hippocampus, and entorhinal cortex. The histaminergic system has been shown to be involved in wakefulness, cognition, food intake, and seizures.

Synthesis
There are multiple synthesis paths for Ciproxifan. One produces the compound through Mitsunobu reaction of imidazolyl trityl-protected 3-(1H-imidazol-4-yl)propanol prepared in four steps from urocanic acid with cyclopropyl 4-hydroxy-phenyl methanone and following acidic deprotection. A simpler synthesis with a lower cost and work expenditure synthesizes Ciproxifan through a nucleophilic exchange reaction between trityl-protected 3-(1H-imidazol-4-yl)propanolate and 4-chloro-4'-fluorobutyrophenone in an excess of sodium hydride, which creates an intermediate that is then worked up by extraction, detritylation, and additional extraction to obtain the final desired product.

Pharmacokinetics
Ciproxifan is a member of a series of potent H3-receptor antagonists, many of which have a high capacity for oral absorption and brain penetration. Thioperamide, another member of this series, was identified as a potential drug for treating psychiatric disorders. However, due to its low bioavailability and liver toxicity, effort was put into finding other safer drugs with higher potency. Ciproxifan appears to be a better option, with an oral bioavailability of 62% and ability to cross the blood brain barrier due to its neutral charge, making oral administration a viable option. Maximal dose of Ciproxifan ranges from 3-10 mg/kg, and can be administered orally, intraperitoneally, or intravenously.

Pharmacodynamics
Ciproxifan is a competitive antagonist/inverse agonist that is highly selective for the H3 receptor. It has an IC50 of 9.2 nM and a Ki value of 1.0 ± 0.3 nM. It has a higher affinity than many related H3 antagonists such as Thioperamide, which has a Ki of about 4 nm, and Carbonperamide, which has a Ki of about 20nm. Ciproxifan acts at the synapse by preventing the autoreceptor H3 from modulating histamine synthesis/release. While it does not directly increase histamine release, the lack of H3 modulation leads to an increased histamine level.

Treatment
Because of the wide influence of the histaminergic system, Ciproxifan has been studied as a treatment for a variety of diseases and conditions, such as obesity, pain, sleep disorders, schizophrenia, attention deficit hyperactivity disorder, Alzheimer's, and cognitive degeneration associated with aging.

Schizophrenia
H3 receptors have connections to the dopaminergic system, for example, showing co-expression with D1 and D2 receptors. Ciproxifan potentiates the effects of antipsychotics, although it does not have antipsychotic properties itself. It has been suggested as an adjunctive medication for schizophrenia, as the positive effects it has on attention and memory may help to treat the cognitive symptoms of schizophrenia.

Sleep Disorders
H1 receptors are known to be involved in sleep/wakefulness states. These receptors are activated by endogenous histamine, which is increased by Ciproxifan. In cats, Ciproxifan has been shown to increase wakefulness by suppressing neocortical slow activity and spindles and increasing neocortical fast rhythms. Increased wakefulness could be helpful in the treatment of narcolepsy or enhancing vigilance in old age.

Alzheimer's Disease
While Ciproxifan is not yet in clinical trials, it may be helpful in the treatment of Alzheimer's Disease. In the amyloid precursor protein transgenic mouse model of Alzheimer's disease, Ciproxifan was shown to improve spatial memory, novel object recognition, and decrease hyperactivity. Since H3 densities do not degenerate through the disease progression, Ciproxifan could prove a valuable treatment throughout the progression of the disease.

Cognitive Enhancement
Because of the importance of the histaminergic system on wakefulness and cognition, Ciproxifan has been looked into for enhancing cognition. In rats, Ciproxifan has been found to increase attentiveness in a serial reaction-time task when a duration of 0.25 seconds was used. Short term memory may also be a target, as Ciproxifan was shown to enhance short term memory in an adult rat social recognition model.

Obesity
While it has not been studied extensively in relation to obesity, Ciproxifan has shown some promise in treating obesity. In a mouse model of diet induced obesity, it was shown to decrease weight gain.

Potential Side Effects
Ciproxifan has not been used in clinical trials, so there are not established side effects in humans. However, as the H3 receptor is also present in the peripheral nervous system, including the gastrointestinal tract, the airways, and the cardiovascular system, it may have unintended effects if it becomes a clinically viable drug. Looking specifically at H3 antagonists, possible adverse side effects could include increased locomotor activity and pituitary hormone secretion, and suppressed food intake.