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

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.

Figure 1

Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) in a model of the histamine H3 receptor. Topology of the H3 receptor model is shown in a membrane bilayer (parallel blue planes). The antagonist binding site, within the trans-membrane core and just below the extracellular loops, is oriented perpendicularly to the membrane, according to the refined binding site of H3 receptor (Levoin et al., 2008). Crucial residues and membrane spanning segments (TM 3-7) are shown in the right inset. Glu206 forms a salt bridge with the piperidine, the hydroxyl of Tyr374 is H-bonded with the central oxygen of the ligand, and Phe198 and/or Tyr189 make π-stacking with the para-chlorophenyl.