Plenary Lecture 6

Title: Histamine H3 Receptor Antagonist – From bench to bedside and back to bench

Professor Holger Stark

Heinrich-Heine University of Düsseldorf, Germany

Lecture Summary:
The role of histamine and histamine receptors in the brain has been recognized a long time ago. With the characterization of the histamine H3 receptor (H3R) subtype its function as neurotransmitter has been proven.1,2 First ligands at H3Rs have been imidazole-containing compounds like thioperamide or ciproxifan. Later on, non-imidazole compounds have been developed.1,3-5 With pitolisant the first potent and selective H3R antagonist has made its way to the market by the approval of the European Medicine Agency (EMA) in March 2016 for the orphan disease narcolepsy with and without cataplexy. Pitolisant (Wakix) has been developed by the French company Bioprojet in cooperation with academic institutes. This partnership gave us the possibility to develop a lot of more lead structures and gave a robust blue print on the pharmacophore structure of H3R antagonists. Actually, clinical trials for the expansion of the therapeutic indication on Parkinson patients are underway.

            Since pitolisant should be used for somnolence and other sleep attacks with dopaminergic therapy on Parkinson´s disease to increase the quality of life, its precognitive effects and influence on other neurotransmitters have initiated the trial of different H3R antagonists in neurodegenerative disease.6,7 Very recently we have observed that ciproxifan displays moderate monoamine oxidase A (MAO A) and B (MAO B) inhibition with slight preference for MAO B (unpublished results). In the content for combining multiple targeting in one molecule we have addressed the H3R in a nanomolare concentration range in combination with MAO B and some MAO A inhibition. In addition to these triple targeting we have additionally added some acetylcholinesterase and butyrylcholinesterase inhibitory potencies. The new compounds series showed some irreversible binding properties which most probably is caused by the propargyl amine moiety. With the multiple targeting one has to find the optimal combination of properties. A novel compound named contilisant showed the balanced and optimized properties at all targets investigated.8 Since the compound also displayed some radical scavenging properties it is potentially a useful compound for the medical treatment of neurodegenerative diseases like Alzheimer´s and Parkinson´s disease.

Acknowledgments: This work has been kindly supported by the EU COST actions CM1103 and CM1207, and the DFG INST 208/664-1FUGG.


References: [1] P. Panula, P. L. Chazot, M. Cowart, R. Gutzmer, R. Leurs, W. L.S. Liu, H. Stark, R. L. Thurmond, H. L. Haas. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. Pharmacol. Rev. 2015, 67, 601-655

2 S. Micallef, H. Stark, A. Sasse. Polymorphism and Genetic Linkage of Histamine Receptors. Life Sci. 2013, 93, 487-494

3 B. Sadek, H. Stark. Cherry-Picked Ligands at Histamine Receptor Subtypes. Neuropharmacology 2016, 106, 56-73

4 B. Sadek, A. Saad, A. Sadeq, F. Jalal, H. Stark. Histamine H3 Receptor as Potential Target for Cognitive Symptoms in Neuropsychiatric Diseases. Behav. Brain Res. 2016, 312, 415-430.

5 B. Sadek, A. Schreeb, J. S. Schwed, L. Weizel, H. Stark. Drug-Likeness Approach on 2-Aminopyrimidines as Histamine H3 Receptor Ligands. Drug Des. Devlop Ther. 2014, 8, 1499-1513

6 K. Nikolic, D. Agbaba, H. Stark. Pharmacophore Modeling, Drug Design and Virtual Screening on Multi-Targeting Procognitive Agents Approaching Histaminergic Pathways. J. Taiwan. Inst. Chem. E. 2015, 46, 15-29

7 M. A. Khanfar, A. Affini, K. Lutsenko, K. Nikolic, S. Butini, H. Stark. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists. Front. Neurosci. 2016, 10, 201; doi: 10.3389/fnins.2016.00201.

8 O. M. Bautista-Aguilera, V. Luzet, L. Ismaili, P.-L. Joffrin, M. L. Jimeno, M. Chioua, S. Hagenow, J. S. Schwed, R. R. Ramsay, H. Stark, J. Marco-Contelles. Multitarget-Directed Antioxidants for Alzheimer´s Disease Therapy: Combining Histamine H3R Binding with Cholinesterase and Monoamine Oxidase Inhibition. Manuscript submitted.