**Background**
The histamine H3 receptor is a G protein-coupled receptor primarily located on presynaptic neurons, where it acts as an autoreceptor to inhibit the release of histamine and as a heteroreceptor to modulate the release of other neurotransmitters, including acetylcholine, dopamine, and norepinephrine. Due to its critical role in regulating wakefulness, cognition, and various neurological functions, the H3 receptor has become a significant target for the development of treatments for sleep disorders and cognitive impairments. Modulating this receptor through inverse agonism or antagonism can enhance histaminergic neurotransmission, thereby improving alertness and cognitive performance. In this context, we will introduce a potent and selective H3 receptor modulator – Pitolisant.
**Definition**
Pitolisant is a potent and selective nonimidazole inverse agonist at the recombinant human histamine H3 receptor with a $K_i$ value of 0.16 nM.
**In Vitro and In Vivo Studies**
According to the Pitolisant description, this compound acts as a competitive antagonist and inverse agonist. Pitolisant in vitro studies demonstrate that it behaves as a competitive antagonist with a $K_i$ of 0.16 nM and as an inverse agonist with an $EC_{50}$ value of 1.5 nM, exhibiting an intrinsic activity approximately 50% higher than that of ciproxifan. In mouse brain cortical membranes, it displaces $[^{125}I]$iodoproxyfan binding with an $IC_{50}$ of $26.4 \pm 4.5$ nM (deduced $K_i = 14 \pm 1$ nM). In membranes of rat glioma C6 cells stably expressing the human H3 receptor, it shows an $IC_{50}$ of $4.2 \pm 0.2$ nM (deduced $K_i = 2.7 \pm 0.5$ nM). Furthermore, it elicits a dose-dependent decrease of basal-specific $[^{35}S]GTP\gamma S$ binding with an $EC_{50}$ of $1.5 \pm 0.1$ nM. In CHO cells, it inhibits human ERG at a holding potential of -90 mV with an $IC_{50}$ of 1.7 $\mu$M.
Regarding Pitolisant In Vivo activity, administration of a single dose (10 mg/kg) 30 minutes before olanzapine (2 mg/kg) significantly affects immobility time and decreases locomotor activity in the forced swim test (FST) in mice. However, subchronic treatment (15 administrations) of Pitolisant (10 mg/kg) followed by olanzapine equalized locomotor activity and significantly reduced immobility time to control levels in the FST. Additionally, rats given Pitolisant (10 mg/kg) during the conditioning phase showed no significant difference in paired texture preference compared to controls, indicating a lack of place preference. For researchers seeking detailed Pitolisant technical information, these results highlight its complex neuromodulatory effects. In conclusion, Pitolisant is a highly selective nonimidazole inverse agonist of the histamine H3 receptor with significant potential for neurological research.
Keywords
Pitolisant, 362665-56-3, Tiprolisant, Histamine Receptor, Inhibitor, inhibitor, inhibit
References
[1] Ligneau X, et al. BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology. J Pharmacol Exp Ther. 2007 Jan;320(1):365-75.
[2] Dudek M, et al. H3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by olanzapine in mice. Metab Brain Dis. 2016 Oct;31(5):1023-9.
[3] Uguen M, et al. Preclinical evaluation of the abuse potential of Pitolisant, a histamine H? receptor inverse agonist/antagonist compared with Modafinil. Br J Pharmacol. 2013 Jun;169(3):632-44.