Abstract
The histamine H3 receptor (H3R) has been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. In this study, a non-imidazole compound, ZEL-H16, was identified as a novel histamine H3 receptor agonist. ZEL-H16 was found to bind to human H3R with a Ki value of approximately 2.07 nM and 4.36 nM to rat H3R. Further characterization indicated that ZEL-H16 behaved as a partial agonist on the inhibition of forskolin-stimulated cAMP accumulation (the efficacy was 60% of that of histamine) and activation of ERK1/2 signaling (the efficacy was 50% of that of histamine) at H3 receptors, but acted as a full agonist just like histamin in the guinea-pig ileum contraction assay. These effects were blocked by pertussis toxin and H3 receptor specific antagonist thioperamide. ZEL-H16 showed no agonist or antagonist activities at the cloned human histamine H1, H2, and H4 receptors and other biogenic amine GPCRs in the CRE-driven reporter assay. Furthermore, our present data demonstrated that treatment of ZEL-H16 resulted in intensive H3 receptor internalization and delayed recycling to the cell surface as compared to that of control with treatment of histamine. Thus, ZEL-H16 is a novel and potent nonimidazole agonist of H3R, which might serve as a pharmacological tool for future investigations or as possible therapeutic agent of H3R.
Highlights
Histamine, a biogenic amine with multiple physiological effects, exerts its biological activities through four distinct G-proteincoupled receptors (GPCRs) known as the histamine H1, H2, H3, and H4 receptors [1,2]
It has been established that H3 receptor (H3R) associates with the heterotrimeric Gi/o-protein, which leads to a decrease in cAMP formation and PKA activation, and causes the activation of the Akt/GSK-3b axis and ERK1/2 pathways, the inhibition of the Na+/H+ exchanger, and modulation of intracellular calcium upon histamine stimulation [14]
One of the compounds identified, ZEL-H16, whose chemical structure and synthetic routes are shown in Figure 1, triggered a significant increase in receptor internalization as compared to the control compound histamine, behaving as an agonist on H3R internalization
Summary
A biogenic amine with multiple physiological effects, exerts its biological activities through four distinct G-proteincoupled receptors (GPCRs) known as the histamine H1, H2, H3, and H4 receptors [1,2]. The histamine H4 receptor was discovered in 2000 [7], and it has been identified as a potential target for the treatment of inflammatory diseases such as chronic allergies, asthma, atopic dermatitis, and inflammatory bowel diseases [8]. The histamine H3 receptor (H3R) was first identified by Arrang and colleagues in 1983 using a functional assay in which it was found that histamine inhibits its own synthesis and release [9]. The H3R has been shown to act as a presynaptic heteroreceptor on non-histaminergic neurons, inhibiting the release of other neurotransmitters such as acetylcholine, dopamine, norepinephrine, serotonin, and various neuropeptides in both the central and peripheral nervous system [15,16,17]. The H3 receptor has long been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. It is reasonable to believe that H3R agonists could hold therapeutic value for the treatment of human diseases
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