Assessment of pharmacology and potential anti-obesity properties of H<sub>3</sub>receptor antagonists/inverse agonists

Hancock, Arthur A.; Brune, Michael E.

doi:10.1517/13543784.14.3.223

Cited by 72 publications

(45 citation statements)

References 99 publications

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“…This protective effect has recently been demonstrated in a rat SC injury model, where the administration of H 3 R selective agonist ␣-methylhistamine ameliorated signs of injury including edema formation and blood SC barrier permeability (44). The EAE-protective nature of H 3 R, and the mapping of an EAE-modifying locus controlling disease severity and associated weight loss (Eae8) to the genomic interval containing Hrh3 (24,(28)(29)(30), combined with the known role of H 3 R in weight control (31), all provide evidence that Hrh3 is a good candidate gene for Eae8.…”

Section: Discussionmentioning

confidence: 99%

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Teuscher

Subramanian

Noubade

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Histamine (HA), a biogenic amine with a broad spectrum of activities in both physiological and pathological settings, plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. HA exerts its effect through four G protein-coupled receptors designated HA receptor H 1, H2, H3, and H4. We report here that, compared with wild-type animals, mice with a disrupted HA H 3 receptor (H3RKO), the expression of which is normally confined to cells of the nervous system, develop more severe disease and neuroinflammation. We show that this effect is associated with dysregulation of bloodbrain barrier permeability and increased expression of MIP-2, IP-10, and CXCR3 by peripheral T cells. Our data suggest that pharmacological targeting of the H 3R may be useful in preventing the development and formation of new lesions in multiple sclerosis, thereby significantly limiting the progression of the disease.blood-brain barrier ͉ experimental allergic encephalomyelitis ͉ multiple sclerosis H istamine [2-(4-imidazole) ethylamine] (HA) is a ubiquitous mediator of diverse physiological processes including neurotransmission, secretion of pituitary hormones, and regulation of the gastrointestinal and circulatory systems (1). HA is a potent mediator of inflammation and a regulator of innate and adaptive immunity (2). HA exerts its effect through four G proteincoupled receptors [H 1 , H 2 , H 3 , and H 4 receptor, designated according to the chronological order of their discovery (1)].HA is implicated in the pathophysiology of multiple sclerosis (MS) and its animal models, collectively termed experimental allergic encephalomyelitis (EAE). HA and agents causing the release of HA from mast cells, the primary source of HA in the body (3), alter blood-brain barrier (BBB) permeability. Tissue levels of HA correlate with the onset of EAE (4-6). Inhibitors of mast cell degranulation and H 1 R and H 2 R antagonists modify EAE severity (7)(8)(9)(10)(11)(12). Epidemiological data indicate that use of sedating H 1 R antagonists is associated with decreased MS risk (13). In a small pilot study, patients with relapsing-remitting or relapsing-progressive MS given the H 1 R antagonist hydroxyzine remained stable or improved neurologically (14). Microarray analysis revealed that the H 1 R was overexpressed in the chronic plaques of MS patients (15). Moreover, mouse genetic studies have shown that HA, H 1 R, and H 2 R play an important role in regulating encephalitogenic T cell responses and susceptibility to EAE (16-18). The role of H 3 R and H 4 R in EAE and MS has not been studied.H 3 R is not normally expressed by hematopoietic cells; rather, it is expressed presynaptically where it is an inhibitory autoreceptor (inhibits release of HA from histaminergic neurons) and heteroreceptor (inhibits release of other neurotransmitters such as acetylcholine, noradrenaline, dopamine, and 5-HT from nonhistaminergic neurons) (19). Absence of presynaptic inhibition results in failure to limit neurotransmitter rel...

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Section: Discussionmentioning

confidence: 99%

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Teuscher

Subramanian

Noubade

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…[3] The histamine H 3 receptor is an important G protein-coupled receptor, identified in 1983 by Arrang et. al [4] and cloned and characterized in 1999.…”

Section: Introductionmentioning

confidence: 99%

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

Ceras

Cirauqui

Pérez‐Silanes

et al. 2012

European Journal of Medicinal Chemistry

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Abstract:The combination of antagonism at histamine H 3 receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H 3 receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H 3 antagonism affinity. However, since all these derivatives failed to block K ATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H 3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype.

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“…They are predominantly expressed in the brain, where they negatively regulate histamine release, acting as presynaptic autoreceptors (10). Therefore, the therapeutic potential of H3R antagonists͞ inverse agonists for treating obesity has been extensively discussed (12,13). Our previous study using H3R-deficient (H3RKO) mice demonstrated a crucial role for H3Rs in appetite and body-weight regulation (14).…”

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confidence: 99%

“…However, enhanced histamine release was accompanied by obese and hyperphagia phenotypes in H3RKO mice. Moreover, the effects of pharmacological blockade of H3Rs on appetite and energy homeostasis have remained controversial (6,13,(15)(16)(17)(18)(19).…”

mentioning

confidence: 99%

Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus

Yoshimoto

Miyamoto

Shimamura

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with ␣-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.autoreceptor ͉ heteroreceptor ͉ appetite regulation O besity has recently become a matter of great concern, because it is considered one of the highest risk factors for diabetes mellitus, hyperlipidemia, and arteriosclerosis. To maintain body weight, caloric intake and energy expenditure must be balanced, and excessive caloric intake is a leading cause of obesity (1). There is growing evidence that the brain receives and integrates information related to energy status from peripheral tissues and that appetite is under the control of numerous neurotransmitters and hormones, such as neuropeptide Y, melanocortin, leptin, and ghrelin (2, 3)Histamine is a classical inflammatory mediator in peripheral tissues and also functions as a neurotransmitter in the brain. Histamine plays a pivotal role in various physiological functions, such as feeding behavior and energy homeostasis (4). Intracerebroventricular administration of histamine consistently decreases appetite in several species (4). Mice with genes disrupted for histamine H1 receptor or histidine decarboxylase (HDC), a ratelimiting enzyme for histamine synthesis, are prone to becoming obese on a high-fat diet or at advanced age (5-8). Furthermore, several antipsychotic drugs with high affinities for H1 receptors are known to cause weight gain in rodents and humans (9). These results suggest a significant role for histamine and H1 receptors in feeding behavior and body-weight regulation.Histamine H3 receptors (H3Rs) were pharmacologically identified more than a decade ago and recently cloned (10, 11). They are predominantly ex...

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Assessment of pharmacology and potential anti-obesity properties of H₃receptor antagonists/inverse agonists

Cited by 72 publications

References 99 publications

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus

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Assessment of pharmacology and potential anti-obesity properties of H3receptor antagonists/inverse agonists

Cited by 72 publications

References 99 publications

Central histamine H3receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Central histamine H3receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus

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Product

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Assessment of pharmacology and potential anti-obesity properties of H₃receptor antagonists/inverse agonists

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS

Central histamine H₃receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS