Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

Abstract

With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

Multitarget‐Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases

“…Inhibition of H3R with inverse agonists/ antagonists elevates the levels of neurotransmitters,s uch as acetylcholine (ACh), 5-HT,d opamine,o rn orepinephrine,i n the central nervous system. [11] Although compounds with multipotent profiles,c ombining H3R affinity with cholinesterase (ChE) inhibition, [12,13] antioxidant capacity, [14] or most recently with MAOinhibition, [15] have been reported, [16] MDLs that are able to simultaneously modulate H3R, MAO, and ChE have not been described to date.S uch am ultipotent profile might constitute an innovative therapeutic approach for new molecules targeting neurodegenerative diseases with multiple causes. [10] Thus the procognitive use of H3R antagonists/inverse agonists for the treatment of neurodegenerative diseases is being investigated.…”

“…[10] Thus the procognitive use of H3R antagonists/inverse agonists for the treatment of neurodegenerative diseases is being investigated. [11] Although compounds with multipotent profiles,c ombining H3R affinity with cholinesterase (ChE) inhibition, [12,13] antioxidant capacity, [14] or most recently with MAOinhibition, [15] have been reported, [16] MDLs that are able to simultaneously modulate H3R, MAO, and ChE have not been described to date.S uch am ultipotent profile might constitute an innovative therapeutic approach for new molecules targeting neurodegenerative diseases with multiple causes.…”

Imaging histamine H3 receptors with [18F]FMH3: Test–retest and occupancy studies in the non‐human primate

“…The multi‐functional mechanisms of H3R makes it an appealing target for pharmaceutical research and development of antagonists/inverse agonists drugs that counteract overstimulation at H3R, thereby enhancing histaminergic tone and the downstream release of other neurotransmitters (Brioni, Esbenshade, Garrison, Bitner, & Cowart, ; Khanfar et al, ). Two selective histamine H3R antagonist/inverse agonists, ABT‐239 and ciproxifan, have been evaluated in preclinical studies for the treatment of neurological and cognitive disorders (Esbenshade et al, ; Fox et al, ; Hagenow, Stasiak, Ramsay, & Stark, ; Luo, Wang, Qin, Liu, & Liu, ).…”

Multipotente Liganden mit kombinierter Cholinesterase‐ und Monoaminooxidase‐Inhibition sowie Histamin‐H3R‐Antagonismus bei neurodegenerativen Erkrankungen

“…Erst kürzlich wurde der erste inverse H3R-Agonist, Pitolisant (WAKIX), fürd ie Therapie von Narkolepsie zugelassen;d ie Verbindung wird aktuell in Hinblick auf diverse kognitive Dysfunktionen und Schlafstçrungen diskutiert. [16]), wurde bisher nicht über Verbindungen berichtet, die H3R, MAO und ChE simultan adressieren. [11] Obwohl Substanzen mit multipotenten Wirkprofilen wie H3R-Affinitätk ombiniert mit Cholinesterase(ChE)-Inhibition [12,13] und antioxidativer Kapazität [14] oder, erst kürzlich, MAO-Inhibition [15] bereits beschrieben wurden (siehe die Übersicht in Lit.…”

“…[11] Obwohl Substanzen mit multipotenten Wirkprofilen wie H3R-Affinitätk ombiniert mit Cholinesterase(ChE)-Inhibition [12,13] und antioxidativer Kapazität [14] oder, erst kürzlich, MAO-Inhibition [15] bereits beschrieben wurden (siehe die Übersicht in Lit. [16] [26] ist die hçhere Hydrophilie (MolLogP = 3.7) im Vergleich zu ASS234 (MolLogP = 5.5), was einen verbesserten Wirkstoff-¾hnlichkeitsfaktor bestätigt. Weitere Indizien für die zentrale Verteilung wurde mittels "Parallel-Artificial-Membrane-Permeability"-Assay (PAMPA) nachgewiesen, einem Vorhersageverfahren fürd ie Überwindung der Blut-Hirn-Schranke (siehe die Hintergrundinformationen).…”