The histamine H3 receptor: from discovery to clinical trials with pitolisant.

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Schwartz JC

The histamine H3 receptor: from discovery to clinical trials with pitolisant.

Br J Pharmacol. 2011 Jun;163(4):713-21. doi: 10.1111/j.1476-5381.2011.01286.x.

PubMed ID

21615387 [ View in PubMed

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Abstract

The third histamine receptor was discovered in 1983 by a traditional pharmacological approach, consisting of assessing the inhibitory effect of histamine on its own release from depolarized rat brain slices. The same in vitro test was used to design, in 1987, the first highly selective and potent H3-autoreceptor ligands, the antagonist thioperamide and the agonist (R)alphamethylhistamine which enhances and inhibits, respectively, the activity of histaminergic neurons in brain. The use of these research tools was instrumental in establishing the main functions of cerebral histaminergic neurons, namely their role in maintenance of wakefulness, attention, learning and other cognitive processes. In 1990, the cloning of the gene of the H3-receptor, a member of the superfamily of heptahelical receptors coupled to G proteins, paved the way to the demonstration of the high constitutive activity of the receptor, including its native form, and its participation in the tonic control of histamine release; it also facilitated the development of H3-receptor inverse agonist programs in many drug companies. Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) is the first inverse agonist to be introduced in the clinics. Its wake-promotion activity was evidenced in excessive diurnal sleepiness of patients with narcolepsy, Parkinson's disease or Obstructive Sleep Apnea/Hypopnea, in which this activity is characterized by a mean decrease of the Epworth Sleepiness Scale by about five units. The procognitive activity of this novel class of drugs may also find therapeutic applications in dementias, schizophrenia or attention deficit hyperactivity disorder.

DrugBank Data that Cites this Article

Drugs

Pitolisant

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Pitolisant	Histamine H3 receptor	Protein	Humans	Yes	Antagonist Inverse agonist	Details

Drug Interactions

Drugs	Interaction
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Pitolisant Amitriptyline	The therapeutic efficacy of Pitolisant can be decreased when used in combination with Amitriptyline.
Pitolisant Imipramine	The therapeutic efficacy of Pitolisant can be decreased when used in combination with Imipramine.
Pitolisant Nortriptyline	The therapeutic efficacy of Pitolisant can be decreased when used in combination with Nortriptyline.
Pitolisant Amoxapine	The therapeutic efficacy of Pitolisant can be decreased when used in combination with Amoxapine.
Pitolisant Trimipramine	The therapeutic efficacy of Pitolisant can be decreased when used in combination with Trimipramine.