histamine h3 receptors

..A relationship between the two regulatory processes, possibly via intracellular calcium, seems likely but remains to be investigated at the molecular level...

..A dilator H2 receptor on the smooth muscle cells seems, at least in vitro, to be the most potent mediator of histamine-mediated pulmonary arterial dilatation...

..3H]A-349821 competition studies showed significant differences in the proportions and potencies of high- and low-affinity sites across species, providing new information about the fundamental pharmacological nature of H3 receptors...

..3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders...

Functional interactions between the G protein-coupled dopamine D1 and histamine H3 receptors have been described in the brain...

..It also was found that chloroproxyfan behaved as a full agonist at the rat recombinant receptor. These findings highlight the significance of validating the pharmacology of experimental compounds at both the rat and human H(3) receptors...

..These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod...

..Although some localizations, mainly as auto- or heteroreceptors, are consistent with previous functional studies, the physiological role, if any, of most of these presynaptic or postsynaptic receptors remains to be established...

..These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H(3) autoreceptors...

..Taken together, these findings allow a further appreciation of the histamine H(3) receptor at the molecular level and provide an additional species to assist in the pharmacological assessment of histamine H(3) receptor function...

..This depression was blocked by the selective antagonist of histamine H3 receptors, thioperamide (10 microM). 3...

..The existence of multiple H3 isoforms with different signal transduction capabilities suggests that H3-mediated biological functions might be tightly regulated through alternative splicing mechanisms...

..Inverse agonists may therefore find therapeutic applications, even in the case of diseases involving non-mutated receptors expressed at normal levels...

..These data indicate that the H(3) receptor-deficient mouse represents a valuable model for studying histaminergic regulation of a variety of behaviors and neurotransmitter systems, including dopamine and acetylcholine...

..In this experimental system, H(3) receptors ligands, previously identified as H(3) antagonists, cover the whole spectrum of pharmacological activities, ranging from full inverse agonists to agonists...

..The availability of the human H3 receptor cDNA should greatly aid in the development of chemical and biological reagents, allowing a greater appreciation of the role of histamine in brain function...

..In this paper, we review various molecular aspects of the hH(3)R including its signal transduction, dimerization and the occurrence of different H(3)R isoforms...

....

Activation of histamine H3 receptors (H3Rs) reduces inflammation and nociception, but the existence of H3Rs on peripheral innervation has never been demonstrated...

BACKGROUND: Although the roles of histamine H3 receptors have been studied in several tissues such as the brain, lung, spleen, colon and peripheral sensory nerve endings, the involvement of H3 receptors in skin responses particularly in ..

..38+/-0.05) in a paired-pulse paradigm. Taken together, our results confirm the presence of H(3)Rs on thalamic nerve terminals and show that their activation modulates pre-synaptically glutamatergic, but not GABAergic neurotransmission...

..The potent regulation of 5-HT by H3Rs reported here not only elucidates HA function in the SNr but also raises the possibility of novel targets for basal ganglia therapies...

..These results indicate that constitutive activity of H3 receptors in rat brain cortex inhibits the adenylate cyclase/PKA pathway, and perhaps also the opening of N-type voltage sensitive calcium channels, but apparently not CaMKII...

..The present data show that the inhibitory action of the afferent neurons discharge previously described for BH is not restricted to this molecule but is also shared by other H3 antagonists...

b>Histamine H3 receptors (H3Rs) are autoreceptors that negatively regulate the release of histamine and other neurotransmitters such as norepinephrine, dopamine, and acetylcholine in the central nervous system (CNS)...

..Our data show that both frog and mouse vestibular epithelia express H1 receptors. Conversely no clear evidence for H3 receptors expression was found...

Pharmacological activation of histamine H3 receptors is known to reduce the release of inflammatory peptides, thereby reducing pain and inflammation, but the site(s) and mechanism(s) of these effects are currently unknown...

..To assess the expression of H3 histamine receptors in vestibular neurons, we performed mRNA RT-PCR and immunofluorescence experiments in mouse Scarpa's ganglia...

..07, pEC(50) = 9.74) with a 300-fold selectivity over the closely related H(4) receptor...

..Mutating the 3' splice site of the longer alternative intron resulted in almost complete splicing of the intron and made the corresponding isoform to become the nearly exclusive transcript in the rat minigene...

..In light of the genetic, pharmacological and functional complexity of the H3 receptor, the importance of the histamine system as a therapeutic target to control the sleep-wake cycle and cognitive disorders will be discussed...

..The corresponding histamine H(3) receptor isoforms as reported for the guinea pig and rat histamine H(3) receptor in different brain regions are not found in the human brain...

..In addition, H3 receptor agonists can be useful as a novel therapeutic approach against pruritus...

..This action on the histaminergic system could explain the effectiveness of betahistine in the treatment of vertigo and vestibular disease...

..Moreover, replacement of the piperidine ring of immepip by a pyrrolidine ring led to a pair of enantiomers that show a distinct stereoselectivity at the human H(3) and H(4) receptor...

..We concluded that histamine suppresses the N- and P-type Ca2+ channels in histaminergic neurons through an H3 receptor which is linked to a pertussis toxin-sensitive G-protein...

..The discovery of the GPRv53 receptor will open a new phase of research on the physiological role of histamine...

..Our data suggest that pharmacological targeting of the H3R may be useful in preventing the development and formation of new lesions in multiple sclerosis, thereby significantly limiting the progression of the disease...

..During vestibular compensation, histaminergic modulation of glycine and GABA release may contribute to the rebalancing of neural activity in the vestibular nuclei of the lesioned and intact sides...

....

..g. pyramidal cells in the cerebral cortex or cerebellar Purkinje cells, in some instances already known to express other histamine receptor subtypes...

..These results suggest that neuronal histamine is a mediator of body-weight homeostasis and that neuronal histamine functions through H3 receptors in mice...

..Findings indicate direct coordination of these imidazole-containing H(3) receptor antagonists with the heme moiety of human adrenal cytochrome P450 isozymes...

..Inasmuch as excessive NE release is clinically recognized as a major cause of arrhythmic cardiac dysfunction, our findings reveal a significant cardioprotective role of H(3)R on cSNE...

..e. mechanical vs. thermal) inhibition of nociception by these receptors, and to assess the efficacy of spinally delivered histamine H(3) receptor agonists for the treatment for pain...

..In both of these assays, SP9144 exhibited evidence of constitutive activation. Taken together, these data demonstrate that SP9144 is a unique, fourth histamine receptor subtype...

....

..A dopamine-independent way seems also to be involved in the histamine-evoked acetylcholine release...

....

..b>Histamine H3 receptors were shown to exhibit both histamine-activated and constitutive GTP-gamma-S-binding activity in the ground ..

..This effect can partially overlap with the expression of the hyperactivity induced by H1-receptor activation. The participation of H2-receptors requires further investigation...

..It is suggested that the studied receptors represent either an avian-specific H(2) -like HA receptors or a novel subtype of HA receptors...

..These results indicate a role for endogenous histamine in modulating the cholinergic tone in the hippocampus...

We tested drugs acting at histamine H3 receptors in mice on the gastrointestinal transit of a charcoal meal in vivo and on neurogenic contractions of isolated ileal preparations...

..CONCLUSIONS: NAMH, which is produced in the gastric mucosa by H pylori, is a potent H2R agonist as well as a H3R agonist...

..Thus, these novel H(3)-receptor antagonists are interesting leads for further development...

..Additionally, selected compounds were functionally investigated in vitro on isolated organs of the guinea-pig at H(3), H(1), and H(2) receptors...

..The data indicate that histaminergic neuromodulation acts predominantly via H-1 receptors...

....

..In addition, histamine and, to a lesser extent substance P are involved in the reaction...

..In conclusion, nefopam analgesic activity is not mediated by histamine H1 or H2 receptors, but can be slightly modulated by histamine H3 receptors in mouse pain tests.

..In the present study the hypothesis was tested that peripheral histamine H3 receptors are involved in the mediation of RH in the intestinal circulation...

..CONCLUSIONS: A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H1-receptor agonists lacking a basic side chain...

..Unexpectedly, some of the novel antagonists also showed a slight preference for the human histamine H(3) receptor compared to their affinities for the guinea-pig H(3) receptor...

..Therefore our findings suggest that the histaminergic system may modify the discriminative stimulus effects of cocaine and methamphetamine mediated through H1- and H3-receptors...

..4) (apparent lipophilicity at pH 7.4) and DeltalogPoct-dce (a descriptor of H-bond donor capacity) allowed to model brain permeation of the majority of the compounds examined...

..07-0.1 mg/kg depending on tissue)...

....

..Furthermore, GAD-67 mRNA levels were not significantly modified by these treatments...

..The effect of histidine on pentylenetetrazole-induced seizures was investigated in rats...

..These results clearly illustrate the efficacy of the H3 autoreceptor in modulating stimulated histamine release during natural stimulatory conditions...

..Our results suggest that histaminergic neurons protect the developing hippocampus from KA-induced neuronal damage, with regulation of neuronal survival being at least partly mediated through H1 and H3 receptors...

..Finally, we quantified binding to histamine H3 receptors (H3Rs) in the medial vestibular nucleus (VN) by means of a histamine H3R agonist ([3H]N-alpha-..

..Such effects of THP were reversed by RAMH indicating the involvement of histamine H(3)-receptors. Findings suggest a potential for H(3)-receptor antagonists in improving the refractory cases of schizophrenia...

..These results show that when the structure of the target protein is unknown, the stereochemical diversity-oriented approach can be a powerful strategy in medicinal chemical studies...

..These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders...

..On the basis of the present study, we believe that histaminergic systems may augment dyskinesias induced by dopamine receptor agonists, independent of direct actions on dopaminergic neurons...

..These histamine receptors resemble those of higher vertebrates and they provide a useful model for pharmacological and behavioral studies for characterizing the functions of histamine in more detail...

..However, the autoradiographic and cellular expression patterns observed in several brain areas such as the thalamus or hippocampus reveal important differences between the two species...

Using the histamine H3 receptor antagonist clobenpropit, the roles of histamine H3 receptors in NMDA-induced necrosis were investigated in rat cultured cortical neurons...

..e. those linked to intracellular G-protein, comprise a subset of the total receptor antagonist-binding sites in the basal ganglia, as has been reported for dopamine D(2) receptors...

....

..However, the reversal effect of (R)alpha-MeHA was prevented by the CCKB/gastrin receptor antagonist PD134308. These results support H3-receptor regulation of basal and cholinergically-stimulated GR and SR...

..These data may form the basis of identification of new targets to treat inflammatory and functional gut disorders...

..Thus, GT-2331 displayed the spectrum of pharmacological activities from full agonism to full antagonism, these observations suggest that histamine H(3) receptor ligands need to be carefully evaluated in various paradigms...

..The antidepressant effect of thioperamide appears to be mediated via serotonergic and/or antioxidant mechanisms...

....

..Histamine induces chemotaxis and IL-12p70 suppression via different receptors using different signaling pathways, which might be important for the pathogenesis of and therapeutic interventions in allergic diseases...

..Our data suggest that the H3-receptor is involved in basal feeding. They also suggest that CCK satiety depends upon the release of histamine which acts on the H2- and H1-receptors, the final mediators of this effect...

....

....

..effect on gastric mucosa against stress-induced gastric ulcers; and (3) ablation of sensory nerves aggravates stress-induced gastric ulcer and reduces histamine-evoked gastroprotection related to stimulation of histamine H3 receptors.

..These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones...

..A protonated N atom in the side chain is not necessary for agonism at H(3) receptors, proposing a receptor-ligand interaction different from that of classical agonists...

..Thus functional histamine H3 receptors, possibly located on renal noradrenergic nerve endings, may play the role of inhibitory modulators of ..

..The implications for potential long-term treatment with H(3) receptor antagonists in CNS disorders such as ADHD are discussed...

..This study demonstrates that betahistine and thioperamide strongly improve the recovery of vestibular functions in UVN cats by interacting with the histaminergic system...

..Although further clarification is needed, these results suggest that some histamine H(3) receptor antagonists may promote the release of neuronal histamine, but also act to reduce histamine methylation in vivo by an unknown mechanism...

..These studies will therefore have implications for understanding metabolic disorders, such as obesity and diabetes, as well as sleep disorders such as excessive day sleepiness and narcolepsy. ..

..These studies will therefore have implications for understanding metabolic disorders, such as obesity and diabetes, as well as sleep disorders such as excessive day sleepiness and narcolepsy. ..

..These studies are expected to provide important insights into neuro-immune signals that result in altered secretory states associated with inflammatory diseases...

..Synthetic methods developed in this proposal are also flexible to make many potentially more potent analogs, which may cure human diseases more effectively. ..

..Synthetic methods developed in this proposal are also flexible to make many potentially more potent analogs, which may cure human diseases more effectively. ..

..studies performed since the original application that thioperamide, a highly selective antagonist at histamine H3 receptors, clearly alleviates injury-induced deficits in spatial working memory...

....

..Accordingly, the proposed studies will generate novel and significant information towards the development of new therapeutic strategies in cardiovascular diseases. ..

..abstract_text> ..

....

..It is imperative that the EDRF system be thoroughly investigated in relation to cardiac HA release...

..The general objective of this investigation is to elucidate novel mechanisms of cardioprotection designed to attenuate the local release of renin and norepinephrine and alleviate cardiac dysfunction. ..

..abstract_text> ..

..These experiments will help to discover the mechanism of action of this novel class of agents, and lead to the development of new pharmacotherapies for pain. ..

..These collaborative experiments between pharmacologists, neurophysiologists and chemists will discover the mechanism of action of this novel class of agents and lead to the development of new, non-opioid pharmacotherapies for pain. ..

..This proposal will uncover new biochemical mechanisms for pain relief, and test a new group of chemicals for pain-relieving properties. This research could lead to the development of new, non-addicting pain relievers. ..

..These studies will clarify the mechanisms by which MOR relieves pain, enhance the understanding of histaminergic antinociceptive mechanisms, and may lead to the discovery of non-addicting, novel medications for the treatment of pain. ..

....

..These studies will enhance our knowledge of antinociceptive mechanisms, and may lead to the development of novel, clinically useful agents for the relief of pain...

..e. nasal provocation) as the means to evaluate future treatments of CFS. ..

..abstract_text> ..

..In this regard, GPCRs are one of the most tractable set of targets for the development of clinically effective, small molecule pharmaceuticals. Of the drugs used clinically in man ~50% target GPCRs. ..

..These methods and biomarkers may be of diagnostic value. They will be useful for assessing longitudinal changes in disease severity, phenotype, or the effects of treatment. ..

....

....

..abstract_text> ..

..D2Orch3CT3 recombinant congenic mice to narrow down the support interval encoding the locus to a size amenable to positional cloning (less than 1 cM), and 2) construct a yeast artificial chromosome (YAC) contig encompassing Orch3. ..

....

....

....

..The results will provide important new information about the dynamic nature of the striatal [DA]ext and its regulation by therapeutic agents of neuropsychiatric disorders. ..