Pitolisant

Signalling of histaminergic neurons plays a key role in activating the arousal system with widespread projections to the whole brain via activating orexin receptors. Narcolepsy is characterized by insufficient neurotransmission by orexins, or hypocretins, which are excitatory peptides released by neurons located from the lateral hypothalamus. These neurons project to aminergic neurons, such as histaminergic or noradrenergic neurons, that are responsible for the effects of orexin and control of wakefulness. Histamine H3 receptors are presynaptic inhibitory autoreceptors that are located in the cerebral cortex, hypothalamus, hippocampus, and basal ganglia. H3 receptors promote the re-uptake of histamine at synaptic terminals and attenuate further histamine release into the synapse. By blocking H3 autoreceptors and increasing the levels of histamine transmitters at the synapse, pitolisant enhances the activity of histaminergic neurons and promotes wakefulness. Inverse agonism of pitolisant at H3 receptors also leads to enhanced synthesis and release of endogenous histamine over the basal level.

Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human H3 receptor and mediates its pharmacological action at the presynaptic level. It is thought to bind to the antagonist binding site of the H3 receptor, which is located within the transmembrane core just below the extracellular loops. Piperidines form a salt bridge with Glu206 in the membrane-spanning segment, and the hydroxyl of Tyr374 is H-bonded with the central oxygen of piperidine. Pitolisant displays high selectivity for H3 receptors compared to other histamine receptor subtypes. Pitolisant also modulates acetylcholine, noradrenaline and dopamine release in the brain by increasing the levels of neurotransmitters but does not increase dopamine release in the stratal complex, including the nucleus accumbens. At lower nanomolar concentrations, pitolisant acts as an inverse agonist at H3 receptors and enhances the release of endogenous histamine over the basal level.