Histamine H3 receptor antagonists/inverse agonists: Where do they go?

Ghamari, Nakisa; Zarei, Omid; Arias‐Montaño, José‐Antonio; Reiner, David J.; Dastmalchi, Siavoush; Stark, Holger; Hamzeh‐Mivehroud, Maryam

doi:10.1016/j.pharmthera.2019.04.007

Cited by 56 publications

(59 citation statements)

References 164 publications

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“…Genetic and pharmacological studies in various animal models also point to the potential of histamine H3 modulation as a novel therapeutic treatment. Pitolisant, an inverse histamine H3 agonist, has recently been approved for the treatment of narcolepsy and a number of clinical trials for other neuropsychiatric conditions are currently underway 10 . Here, we show for the first time that hrh3 deletion reduces aggressive behaviour, which might lead to a novel therapeutic treatment for human conditions characterized by excessive aggression.…”

Section: Resultsmentioning

confidence: 68%

“…The histamine H3 receptor is an emerging, promising therapeutic target for a variety of psychiatric disorders 10 . It is widely expressed in the brain, and has an important neurophysiological role in regulating the signalling of histaminergic neurons as well as other neurotransmitter systems in mammals 8 .…”

Section: Discussionmentioning

confidence: 99%

“…The histamine H3 receptor (Hrh3) has recently gained attention in studies of behaviour and neuropsychiatric disease 8‐10 . Hrh3 is expressed predominantly in important brain areas such as the cortex, thalamus, hypothalamus, hippocampus, amygdala and basal ganglia 8 .…”

Section: Introductionmentioning

confidence: 99%

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The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity

et al. 2020

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Aim Aggression is a behavioural trait characterized by the intention to harm others for offensive or defensive purposes. Neurotransmitters such as serotonin and dopamine are important mediators of aggression. However, the physiological role of the histaminergic system during this behaviour is currently unclear. Here, we aimed to better understand histaminergic signalling during aggression by characterizing the involvement of the histamine H3 receptor (Hrh3). Methods We have generated a novel zebrafish Hrh3 null mutant line using CRISPR‐Cas9 genome engineering and investigated behavioural changes and alterations to neural activity using whole brain Ca2+ imaging in zebrafish larvae and ribosomal protein S6 (rpS6) immunohistochemistry in adults. Results We show that genetic inactivation of the histamine H3 receptor (Hrh3) reduces aggression in zebrafish, an effect that can be reproduced by pharmacological inhibition. In addition, hrh3−/− zebrafish show behavioural impairments consistent with heightened anxiety. Larval in vivo whole brain Ca2+ imaging reveals higher neuronal activity in the forebrain of mutants, but lower activity in specific hindbrain areas and changes in measures of functional connectivity between subregions. Adult hrh3−/− zebrafish display brain region‐specific neural activity changes in response to aggression of both key regions of the social decision‐making network, and the areas containing histaminergic neurons in the zebrafish brain. Conclusion These results highlight the importance of zebrafish Hrh3 signalling for aggression and anxiety and uncover the brain areas involved. Targeting this receptor might be a potential novel therapeutic route for human conditions characterized by heightened aggression.

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Section: Resultsmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity

et al. 2020

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“…There are some H 3 R antagonists in clinical trial studies for which their effectiveness in AD is being evaluated as mono‐ or add‐on therapy. The examples of such clinical candidates are ABT‐288, AZD‐5213, GSK‐239512, GSK‐1004723, MK‐0249, and S 38093 (for more details, see Ghamari et al, ). Recently, several studies have focused on developing ligands targeting both H 3 Rs and cholinesterase enzymes (Bajda et al, ; Bembenek et al, ; Darras et al, ; Incerti et al, ; Lazewska et al, ; Sadek, Khan, et al, ), since the synergistic effect of these agents leads to enhance cholinergic neurotransmission through different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H₃ receptors and cholinesterase enzymes

et al. 2019

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Recently, multi-target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H 3 receptors (H 3 Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual-acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H 3 R antagonistic activity combined with anticholinesterase properties of two previously computationally identified leadpropyl]-1H-indole-2-carboxamide) and compound 4 (7-chloro-N-[(1-methylpiperidin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide), was tested.Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (com-pound 3: H 3 R EC 50 = 0.73 nM; compound 4: H 3 R EC 50 = 31 nM) and micromolar values (compound 3: AChE IC 50 = 9.09 µM, BuChE IC 50 = 21.10 µM; compound 4: AChE IC 50 = 8.40 µM, BuChE IC 50 = 4.93 µM) for H 3 R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H 3 R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy. K E Y W O R D S anticholinesterase, anti-H 3 R agents, histamine H 3 receptor, molecular docking, molecular dynamics simulation, multi-target directed ligands 280 | GHAMARI et Al.

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“…17 While concentrated in the central nervous system (CNS), the H3R can also be found in the pulmonary, gastrointestinal and cardiovascular systems. 18 It is also present on axon terminals of non-histaminergic neurons (heteroreceptors) and has an inhibitory effect on the release of other neurotransmitters, particularly norepinephrine, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and glutamate. H3Rs remain constitutively active resulting in a continued inhibitory effect even in the absence of histamine.…”

Section: Pathophysiology Of Narcolepsymentioning

confidence: 99%

<p>Pitolisant to Treat Excessive Daytime Sleepiness and Cataplexy in Adults with Narcolepsy: Rationale and Clinical Utility</p>

Guevarra

Hiensch

Varga

et al. 2020

NSS

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Narcolepsy is a sleep disorder marked by chronic, debilitating excessive daytime sleepiness and can be associated with cataplexy, sleep paralysis and sleep-related hallucinations. Pharmacological therapy for narcolepsy primarily aims to increase wakefulness and reduce cataplexy attacks. Pitolisant is a first-in-class agent utilizing histamine to improve wakefulness by acting as an antagonist/inverse agonist of the presynaptic histamine 3 receptor. This review summarizes the clinical efficacy, safety and tolerability of pitolisant in treating the symptoms of narcolepsy. Randomized and observational studies demonstrate pitolisant to be effective in treating both hypersomnolence and cataplexy while generally being well tolerated at prescribed doses. The most common adverse reactions include headache, insomnia and nausea.

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Histamine H3 receptor antagonists/inverse agonists: Where do they go?

Cited by 56 publications

References 164 publications

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H₃ receptors and cholinesterase enzymes

<p>Pitolisant to Treat Excessive Daytime Sleepiness and Cataplexy in Adults with Narcolepsy: Rationale and Clinical Utility</p>

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Histamine H3 receptor antagonists/inverse agonists: Where do they go?

Cited by 56 publications

References 164 publications

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity

In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes

<p>Pitolisant to Treat Excessive Daytime Sleepiness and Cataplexy in Adults with Narcolepsy: Rationale and Clinical Utility</p>

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In silico and in vitro studies of two non‐imidazole multiple targeting agents at histamine H₃ receptors and cholinesterase enzymes