Related Experiment Video
Updated: May 28, 2026

Stepwise Dosing Protocol for Increased Throughput in Label-Free Impedance-Based GPCR Assays
Published on: February 21, 2020
Several down, a few to go: histamine H3 receptor ligands making the final push towards the market?
Sebastiaan Kuhne1, Maikel Wijtmans, Herman D Lim
1VU University Amsterdam, Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
Introduction:
The histamine H(3) receptor (H(3)R) plays a pivotal role in a plethora of therapeutic areas. Blocking the H(3)R with antagonists/inverse agonists has been postulated to be of broad therapeutic use. Indeed, H(3)R antagonists/inverse agonists have been extensively evaluated in the clinic.
Areas Covered:
Here, we address new developments, insights obtained and challenges encountered in the clinical evaluations. For recent H(3)R clinical candidates, the status and results of the corresponding clinical trial(s) will be discussed along with preclinical data.
Main Findings:
In all, it becomes evident that clinical evaluation of H(3)R antagonists/inverse agonists is characterized by mixed results. On one hand, Pitolisant has successfully passed several Phase II trials and seems to be the most advanced compound in the clinic now, being in Phase III. On the other hand, some compounds (e.g., PF-03654647 and MK-0249) failed at Phase II clinical level for several indications.
Expert Opinion:
A challenging feature in H(3)R research is the multifaceted role of the receptor at a molecular/biochemical level, which can complicate targeting by small molecules at several (pre)clinical levels. Accordingly, H(3)R antagonists/inverse agonists require further testing to pinpoint the determinants for clinical efficacy and to aid in the final push towards the market.
Related Concept Videos
Acid Suppressive Drugs for Peptic Ulcer Disease: Histamine H2-Receptor Antagonists
Drug-Receptor Interaction: Agonist
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous ligand's action.
Upper Respiratory Drugs: First and Second-Generation Antihistamines
Histamine binds to specific receptor sites, known as H1 receptors, on tissue cells, triggering inflammation and swelling. Antihistamines combat these effects by competing with histamine for these receptor sites. By...
Drugs Affecting GI Tract Motility: Serotonin Receptor Agonists
Spare Receptors
Antiasthma Drugs: Mast Cell Stabilizers and Anti-IgE Drugs
Mast cell stabilizers, such as cromolyn (also known as sodium cromoglycate) and nedocromil (Tilade), are effective drugs in asthma management. These stabilizers hinder histamine release by skillfully obstructing the activation of mast cells and other cellular entities. Notably, they navigate this task without...

