The histamine H3 receptor as a therapeutic drug target for CNS disorders

Gemkow, Mark J.; Davenport, Adam J.; Harich, Silke; Ellenbroek, Bart A.; Cesura, Andrea M.; Hallett, David J.

doi:10.1016/j.drudis.2009.02.011

Cited by 169 publications

(128 citation statements)

References 60 publications

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“…H 3 R antagonists/inverse agonists have been shown to increase wakefulness, improve cognitive performances and reduce body weight in animal models [6]. Such findings hint at the potential use of these compounds for the treatment of Alzheimer's disease (AD) and other dementias, attention-deficit hyperactivity disorder (ADHD), cognitive deficits in schizophrenia, obesity and sleep disorders [45,[49][50][51]. Thus, it is not surprising that much effort is focused on the development of clinically suitable H 3 R antagonists/inverse agonists by academic and industrial laboratories [45,51,52].…”

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confidence: 99%

“…Such findings hint at the potential use of these compounds for the treatment of Alzheimer's disease (AD) and other dementias, attention-deficit hyperactivity disorder (ADHD), cognitive deficits in schizophrenia, obesity and sleep disorders [45,[49][50][51]. Thus, it is not surprising that much effort is focused on the development of clinically suitable H 3 R antagonists/inverse agonists by academic and industrial laboratories [45,51,52]. As a result, more and more H 3 R antagonists/inverse agonists, such as ABT-239…”

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confidence: 99%

“…Network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms. Thus, the regulatory role in the release of histamine and other neurotransmitters makes the H 3 R an attractive target for therapies of CNS disorders, and H 3 R ligands are good therapeutic candidates for their simultaneous exploitation of multiple neuronal systems [45,46]. Consistent with the widespread distribution throughout the entire CNS of histaminergic fibers [47,48], brain histamine is, directly or indirectly, involved in a variety of basic homeostatic and higher brain functions, such as the sleep-wake cycle, appetite, noci ception, cognition and emotion [1,6].…”

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confidence: 99%

“…propoxy]propyl}piperidine, hydrochloride; GSK-239512 (structure not disclosed); JNJ-17216498 (structure not disclosed); MK-0249 (structure not disclosed) and PF-03654746 (trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutanecarboxamide), progress through the clinic for a variety of conditions, including ADHD, cognitive disorders, h yperalgesia, n arcolepsy and schizophrenia [45].…”

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confidence: 99%

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Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Blandina¹,

Munari

Giannoni

et al. 2010

Future Neurol.

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Much has been learned over the past 20 years about the role of histamine as a neurotransmitter. This brief article attempts to evaluate the progress accomplished in this field, and discusses the therapeutic potential of the H3 receptor (H3R). All histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus and project to almost all regions of the CNS. Histamine exerts its effect via interaction with specific receptors (H1R, H2R, H3R and H4R). Antagonists of both H1R and H2R have been successful as blockbuster drugs for treating allergic conditions and gastric ulcers. H4R is still awaiting better functional characterization, but the H3R is an attractive target for potential therapies of CNS disorders. Indeed, considerable interest was raised by reports that pharmacological blockade of H3Rs exerted procognitive effects in a variety of animal tasks analyzing different types of memory. In addition, blockade of H3Rs increased wakefulness and reduced bodyweight in animal models. Such findings hint at the potential use of H3R antagonists/inverse agonists for the treatment of Alzheimer’s disease and other dementias, attention-deficit hyperactivity disorder, obesity and sleep disorders. As a result, an increasing number of H3R antagonists/inverse agonists progress through the clinic for the treatment of a variety of conditions, including attention-deficit hyperactivity disorder, cognitive disorders, narcolepsy and schizophrenia. Moreover, the use of H3R antagonists/inverse agonists that weaken traumatic memories may alleviate disorders such as post-traumatic stress syndrome, panic attacks, specific phobias and generalized anxiety. The use of H3R ligands for the treatment of neurodegenerative disorders is demonstrated in several studies, indicating a role of the histamine neurons and H3Rs in neuroprotection. Recently, direct evidence demonstrated that histaminergic neurons are organized into functionally distinct circuits, impinging on different brain regions, and displaying selective control mechanisms. This could imply independent functions of subsets of histaminergic neurons according to their respective origin and terminal projections. The possibility that H3Rs control only some of those functions implies that H3R-directed therapies may achieve selective effects, with minimal side effects, and this may increase the interest regarding this class of drugs.

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Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Blandina¹,

Munari

Giannoni

et al. 2010

Future Neurol.

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“…Mutual interactions with these other transmitter systems form a network that links basic homeostatic and higher brain functions, including sleep-wake regulation, circadian and feeding rhythms, immunity, attention, learning, and memory (3)(4)(5)(6)(7)(8)(9). H3 receptor IAs may thus be efficacious in the treatment of various CNS disorders (10,11). Pitolisant was the first H3 IA to be introduced in the clinic.…”

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¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

et al. 2013

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The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Methods: Using PET and a novel high-affinity and selective radioligand 11 C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. Results: The mean effective dose for 11 C-MK-8278 was 5.4 6 1.1 mSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. Conclusion: 11 C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules. Hi stamine is an aminergic neurotransmitter that is localized in the central nervous system (CNS) and in peripheral tissues such as the gut, skin, and immune system. In the brain, histaminergic neurons originate in the tuberomammillary nucleus of the hypothalamus and project throughout the CNS, including the thalamus, hypothalamus, cerebral cortex, striatum, medulla oblongata, and spinal cord. There are 4 known G-protein-coupled histamine receptor subtypes (H1-H4). These serve multiple functions in the brain, particularly control of excitability and plasticity. Type 1 and 2 histamine receptor-mediated actions are mostly excitatory. The H3 receptor was discovered in 1983 and cloned at the end of the twentieth century (1) and is mainly expressed in the CNS. H3 receptors predominate in the basal ganglia, with the highest densities in the globus pallidus (2). The H3 receptor is a presynaptic inhibitory autoreceptor that regulates the synthesis and release of histamine and also modulates the release of several other neurotransmitters such as acetylcholine, norepinephrine, serotonin, dopamine, and g aminobutyric acid. Like other G-protein-coupled receptors, H3 receptors signal constitutively, serving to tonically suppress histamine production at baseline. Agonist-induced signaling, such as that which occurs in the presence of elevated histamine levels, further suppresses histamine...

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Dual‐Acting Diether Derivatives of Piperidine and Homopiperidine with Histamine H₃ Receptor Antagonistic and Anticholinesterase Activity

Bajda

Kuder

Łażewska

et al. 2012

Archiv der Pharmazie

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The study presents novel biological properties of diether derivatives of homo- or substituted piperidine ligands of the histamine H(3) receptor. The compounds were evaluated for their inhibitory potency against acetylcholinesterase (AChE) from the electric eel and butyrylcholinesterase (BuChE) from horse serum. The most interesting multifunctional compound 13 displayed high affinity for the cloned hH(3) R (K(i) = 3.48 nM) and moderate inhibitory potency against both enzymes (IC(50) AChE = 7.91 µM and BuChE = 4.97 µM). Molecular modeling studies revealed interactions with key amino acid residues in the homology model of histamine H(3) receptor ligands, as well as the binding model for AChE and BuChE in the catalytic and peripheral active sites.

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The histamine H3 receptor as a therapeutic drug target for CNS disorders

Cited by 169 publications

References 60 publications

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

Dual‐Acting Diether Derivatives of Piperidine and Homopiperidine with Histamine H₃ Receptor Antagonistic and Anticholinesterase Activity

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The histamine H3 receptor as a therapeutic drug target for CNS disorders

Cited by 169 publications

References 60 publications

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

Histamine neuronal system as a therapeutic target for the treatment of cognitive disorders

11C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

Dual‐Acting Diether Derivatives of Piperidine and Homopiperidine with Histamine H3 Receptor Antagonistic and Anticholinesterase Activity

Contact Info

Product

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About

¹¹C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

Dual‐Acting Diether Derivatives of Piperidine and Homopiperidine with Histamine H₃ Receptor Antagonistic and Anticholinesterase Activity