Conformational Restriction of Histamine with a Rigid Bicyclo[3.1.0]hexane Scaffold Provided Selective H3 Receptor Ligands

We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H3 receptors (Ki = 5.6 nM for H3 and 602 nM for H4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.

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Evaluation of Histamine H1-, H2-, and H3-Receptor Ligands at the Human Histamine H4 Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H4 Receptor Agonist

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.105.087965 ◽

2005 ◽

Vol 314 (3) ◽

pp. 1310-1321 ◽

Cited By ~ 209

Author(s):

Herman D. Lim ◽

Richard M. van Rijn ◽

Ping Ling ◽

Remko A. Bakker ◽

Robin L. Thurmond ◽

...

Keyword(s):

Receptor Agonist ◽

Receptor Ligands ◽

Histamine H4 Receptor ◽

H3 Receptor ◽

H4 Receptor ◽

Human Histamine

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Functional Relationship between Mast Cells and C-Sensitive Nerve Fibres Evidenced by Histamine H3-Receptor Modulation in Rat Lung and Spleen

Clinical Science ◽

10.1042/cs0870151 ◽

1994 ◽

Vol 87 (2) ◽

pp. 151-163 ◽

Cited By ~ 65

Author(s):

V. Dimitriadou ◽

A. Rouleau ◽

M. Dam Trung Tuong ◽

G. J. F. Newlands ◽

H. R. P. Miller ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Feedback Loop ◽

Cell Activity ◽

Receptor Ligands ◽

Histamine H3 Receptor ◽

Mast Cell Protease ◽

H3 Receptor ◽

H3 Receptors ◽

Histamine H3

1. Mast cell populations in rat lung and spleen were characterized by the presence of two specific protease markers, rat mast cell protease I and II, using both histochemical and radioimmunoassay techniques. Three mast cell populations with different size, morphology and localization were found in lung and spleen and were identified according to the expression of rat mast cell protease I (RMCPI+) or rat mast cell protease II (RMCPII+) or of both proteases (RMCPI/II+). 2. All three mast cell types were in the vicinity of calcitonin-gene-related-peptide-immunoreactive (CGRP+) nerve fibres in controls as well as in rats infected by Nippostrongylus brasiliensis in which a large increase in the number of both RMCPII+ and RMCPI/II+ mast cells was found. Ablation of the CGRP+ fibres by neonatal treatment with capsaicin resulted in a marked increase in the number of RMCPII+ and RMCPI/II+ cells in lung and, even more, in spleen of adult rats. 3. The interaction of mast cells with CGRP+ C-fibres was assessed pharmacologically by evaluation of the effects of histamine H3-receptor ligands known to act on various types of nerve endings, including those of C-fibres. The effects of H3-receptor ligands were assessed in controls, nematode-infected rats and neonatally capsaicinized rats. Mast cell activity was evaluated by measurement of [3H]histamine synthesis from [3H]histidine. In control rats, administration of the H3-receptor agonist (R)-α-methylhistamine and antagonist thioperamide, decreased and enhanced respectively [3H]histamine synthesis in lung and spleen, indicating a tonic control of mast cell activity by histamine via H3-receptors. Such effects were not found in the jejunum, although RMCPII+ mast cells are in close apposition with neuropeptide-containing fibres. The effects of the H3-receptor agents were maintained in lung and spleen of nematode-infected rats, but were almost suppressed in capsaicinized rats. 4. It is concluded that the control of mast cells by histamine acting at H3-receptors involves neuropeptide-containing nerves and presumably reflects the operation of a local neuron-mast cell feedback loop controlling processes such as ‘neurogenic inflammation’. This loop still functions when mast cells proliferate in an inflammatory condition. These observations suggest that the use of histamine H3-receptor agonists may constitute a novel therapeutic approach to limit excessive inflammatory responses resulting from dysregulation of this feedback loop.

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Central Histamine, the H3-Receptor and Obesity Therapy

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190703094846 ◽

2019 ◽

Vol 18 (7) ◽

pp. 516-522

Author(s):

Néstor F. Díaz ◽

Héctor Flores-Herrera ◽

Guadalupe García-López ◽

Anayansi Molina-Hernández

Keyword(s):

Body Weight ◽

Food Intake ◽

Animal Studies ◽

Energy Homeostasis ◽

Receptor Activation ◽

Receptor Ligands ◽

Histaminergic System ◽

H3 Receptor ◽

Weight One ◽

The Central Nervous System

The brain histaminergic system plays a pivotal role in energy homeostasis, through H1- receptor activation, it increases the hypothalamic release of histamine that decreases food intake and reduces body weight. One way to increase the release of hypothalamic histamine is through the use of antagonist/inverse agonist for the H3-receptor. Histamine H3-receptors are auto-receptors and heteroreceptors located on the presynaptic membranes and cell soma of neurons, where they negatively regulate the synthesis and release of histamine and other neurotransmitters in the central nervous system. Although several compounds acting as H3-receptor antagonist/inverse agonists have been developed, conflicting results have been reported and only one has been tested as anti-obesity in humans. Animal studies revealed the opposite effect in food intake, energy expeditor, and body weight, depending on the drug, spice, and route of administration, among others. The present review will explore the state of art on the effects of H3-receptor ligands on appetite and body-weight, going through the following: a brief overview of the circuit involved in the control of food intake and energy homeostasis, the participation of the histaminergic system in food intake and body weight, and the H3-receptor as a potential therapeutic target for obesity.

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