The medicinal chemistry and therapeutic potentials of ligands of the histamine H3 receptor

Leurs, Rob; Vollinga, Roeland C.; Timmerman, Henk

doi:10.1007/978-3-0348-7164-8_4

Cited by 35 publications

(40 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The effects of test drugs on tritium outflow, evoked by electrical stimulation, are expressed as S 1 (percentage of the tritium content of the tissue at the onset of the first electrical stimulation) or S 2 /S 1 values (ratio of the percentage release during the second stimulation over that obtained during the first stimulation). Each value represents the mean ± SEM of 5-7 experiments Electrically evoked tritium overflow It is remarkable that, in the present study, very similar EC 50 values were obtained for histamine (33.5 nM) and R-α-methylhistamine (41.6 nM), whereas in other reports R-α-methylhistamine was more potent than histamine (for review, see Leurs et al 1995;Hill et al 1997). At present, we do not have a clear explanation for these differences.…”

Section: Discussionsupporting

confidence: 85%

H 3 receptor-mediated inhibition of intestinal acetylcholine release: pharmacological characterization of signal transduction pathways

Blandizzi

Colucci

Tognetti

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

View full text Add to dashboard Cite

The present study investigates the mechanisms through which prejunctional histamine H3 receptors modulate intestinal cholinergic neurotransmission. The experiments were performed on longitudinal muscle-myenteric plexus preparations of guinea pig ileum, preincubated with [3H]choline, superfused with physiological salt solution containing hemicholinium-3, and subjected to electrical field stimulation. The stimulation-induced outflow of radioactivity was taken as an index of endogenous acetylcholine release. The electrically induced [3H]acetylcholine release was inhibited by histamine (EC50)=33.5 nM) or the H3 receptor agonist R-alpha-methylhistamine (EC50=41.6 nM), whereas it was not affected by pyridylethylamine (H1 agonist), impromidine (H2 agonist), pyrilamine (H1 antagonist), cimetidine (H2 antagonist), thioperamide or clobenpropit (H3 antagonists). The inhibitory effects of histamine or R-alpha-methylhistamine were antagonized by thioperamide (pKd= 8.31 and 8.53, respectively) or clobenpropit (pKd=9.44 and 9.32, respectively), but not by pyrilamine or cimetidine. The modulatory action of histamine on the evoked tritium outflow was attenuated by pertussis toxin and abolished by N-ethylmaleimide, two selective blockers of Gi/Go proteins. Tetraethylammonium or 4-aminopyridine, acting as inhibitors of voltage-dependent K+ channels, enhanced the evoked tritium outflow when tested alone, and apparently counteracted the inhibitory effect of histamine. However, the blocking actions of tetraethylammonium and 4-aminopyridine were no longer evident when their enhancing actions were compensated by appropriate reductions of Ca2+ concentration in the superfusion medium. Histamine-induced inhibition of evoked tritium output was enhanced by omega-conotoxin, a selective blocker of N-type Ca2+ channels, or low Ca2+ concentration, whereas it was not modified by nifedipine, an antagonist of L-type Ca2+ channels. In addition, the inhibitory effect of histamine was not significantly affected by forskolin (activator of adenylyl cyclase), 8-bromo-cyclic AMP (a stable analog of cyclic AMP), rolipram (a selective blocker of type IV phosphodiesterase), phorbol myristate acetate (activator of protein kinase C), H-89 (N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide, inhibitor of protein kinase A), Ro-31-8220 (2-(1-[3-(amidinothio)propyl]-1H-indol-3-yl)-3-(1-methylindol-3-yl)-maleimide, inhibitor of protein kinase C), KT5823 (N-methyl-(8R*,9S*,11S*)-(-)-9-methoxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo [a,g]cycloocta[c,d,e]-trinden-1-one, inhibitor of protein kinase G), or lavendustin A (inhibitor of tyrosine kinase). The present results indicate that histamine inhibits intestinal cholinergic neurotransmission through presynaptic H3 receptors coupled to Gi/Go proteins. It is suggested that adenylyl cyclase, serine-threonine protein kinase and tyrosine kinase pathways are not implicated in this regulatory action, and that Gi/Go proteins modulate the activity of N-type Ca2+ chann...

show abstract

Section: Discussionsupporting

confidence: 85%

H 3 receptor-mediated inhibition of intestinal acetylcholine release: pharmacological characterization of signal transduction pathways

Blandizzi

Colucci

Tognetti

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

View full text Add to dashboard Cite

show abstract

“…Similar to imetit superfusion with the novel H 3 receptor agonist, immepip (Vollinga et al 1994;Leurs et al 1995) enhanced the release of acetylcholine (Fig. 7).…”

Section: Resultsmentioning

confidence: 78%

Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H3 histamine receptors

Prast

Tran

Fischer

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

To investigate whether histaminergic neurons influence the activity of cholinergic neurons, the ventral striatum was superfused through a push-pull cannula and the release of endogenous acetylcholine was determined in the superfusate. Local inhibition of histamine synthesis by superfusion with alpha-fluoromethylhistidine (FMH) gradually decreased the release rate of acetylcholine. Superfusion with histamine increased the release of acetylcholine. The releasing effect of histamine was greatly inhibited when the striatum was simultaneously superfused with the D2/D3 agonist quinpirole and the D1 antagonist (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-3-benzapine (SKF 83566). The effect of histamine on acetylcholine release was abolished by the GABA(A) receptor antagonist bicuculline. Superfusion with the H3 receptor agonists imetit or immepip increased acetylcholine release rate in the striatum. The releasing effects of the two H3 agonists were FMH resistant, while superfusion with quinpirole and SKF 83566 abolished the H3 receptor agonist-induced acetylcholine release. Superfusion with the H3 receptor antagonist thioperamide enhanced acetylcholine release rate. The releasing effect of thioperamide was abolished after inhibition of histamine synthesis by FMH. The release of acetylcholine by thioperamide was also abolished on simultaneous superfusion with quinpirole and SKF 83566. The findings show that, in the striatum, the activity of cholinergic neurons is permanently modulated by neighbouring histaminergic nerve terminals and axons. The release of acetylcholine is also permanently inhibited by neighbouring GABAergic neurons. The enhanced release of acetylcholine by the H3 receptor agonists imetit and immepip is due to stimulation of H3 heteroreceptors, while the increase of acetylcholine release by the H3 receptor antagonist thioperamide is elicited via blockade of H3 autoreceptors. Histamine released from histaminergic nerve terminals increases the release of acetylcholine in part by inhibition of dopamine release which, in turn, decreases GABAergic transmission. A dopamine-independent way seems also to be involved in the histamine-evoked acetylcholine release.

show abstract

“…The extent of the H 3 receptor-mediated inhibition of noradrenaline release is much more marked in the mouse than in the guinea-pig brain cortex. H 3 receptors causing inhibition of noradrenaline release in the CNS appear to be a common phenomenon; they have been identified in vitro in various brain regions of humans, rats, mice (for review, see Arrang et al 1992;Schlicker et al 1994;Leurs et al 1995;Stark et al 1996) and guinea-pigs (present study). On the other hand, H 2 receptors causing facilitation of noradrenaline release could not be shown in the mouse and rat brain cortex in vitro (Schlicker et al 1989(Schlicker et al , 1992a but have been identified in the rat hypothalamus in vitro (Blandina et al 1989) and in the cat posterior hypothalamus in vivo (Philippu et al 1984).…”

Section: Discussionmentioning

confidence: 93%

“…Subsequent studies revealed that in the CNS also the release of noradrenaline, serotonin, dopamine, acetylcholine (for review, see Arrang et al 1992;Schlicker et al 1994;Leurs et al 1995;Stark et al 1996) and probably also that of GABA (Garcia et al 1997) and of glutamate (Brown and Reymann 1996) is inhibited via H 3 receptors. All in vivo studies related to the H 3 receptor-mediated modulation of transmitter release were carried out on rats; the in vitro studies were performed in isolated CNS preparations from rats and, less frequently, from humans and mice (for review, see Arrang et al 1992;Schlicker et al 1994;Leurs et al 1995;Stark et al 1996).…”

Section: Introductionmentioning

confidence: 99%

H2 receptor-mediated facilitation and H3 receptor-mediated inhibition of noradrenaline release in the guinea-pig brain

Timm

Marr

Werthwein

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

The effect of histamine and related drugs on the tritium overflow evoked electrically (0.3 Hz) or by introduction of Ca2+ ions into Ca2+-free K+-rich (25 mmol/l) medium containing tetrodotoxin was studied in superfused guinea-pig brain cortex, cerebellum, hippocampus or hypothalamus slices and in mouse brain cortex slices preincubated with 3H-noradrenaline. The electrically evoked tritium overflow in guinea-pig cortex slices was inhibited by histamine; the H3 receptor antagonist clobenpropit reversed the effect of histamine to a slight facilitation. The facilitatory effect of histamine (obtained in the presence of clobenpropit) was not affected by the H1 receptor antagonist mepyramine but abolished by the H2 receptor antagonist ranitidine. In the absence of clobenpropit, ranitidine augmented the inhibitory effect of histamine. In slices superfused in the presence of ranitidine, the evoked overflow was inhibited by histamine and, more potently, by the H3 receptor agonist R-alpha-methylhistamine in a concentration-dependent manner (maximum inhibitory effect obtained for both agonists 30-35%). The concentration-response curve of histamine was shifted to the right by the H3 receptor antagonist thioperamide. R-alpha-methylhistamine inhibited the electrically evoked tritium overflow also in guinea-pig cerebellar, hippocampal and hypothalamic slices. In cortex slices superfused in the presence of clobenpropit, the H2 receptor agonists impromidine and, less potently, R-sopromidine facilitated the evoked overflow in a concentration-dependent manner. S-Sopromidine only tended to increase the evoked overflow. The effect of impromidine was counteracted by the H2 receptor antagonists ranitidine and cimetidine. The extent of the maximum facilitatory effect of impromidine (by 15-20%) was about the same when (i) the Ca2+ concentration in the medium was reduced from 1.3 to 0.98 mmol/l, (ii) the time of exposure to impromidine was reduced from 28 to 8 min or (iii) cerebellar, hippocampal or hypothalamic slices were used instead of cortical slices. The Ca2+-induced tritium overflow in guinea-pig cortex slices was inhibited by histamine (in the presence of ranitidine); this effect was abolished by clobenpropit. In slices superfused in the presence of clobenpropit, impromidine failed to facilitate the Ca2+-evoked tritium overflow. The electrically evoked tritium overflow in mouse brain cortex slices was inhibited by histamine by about 60% (both in the absence or presence of ranitidine). The inhibitory effect of histamine was abolished (but not reversed) by clobenpropit. In conclusion, noradrenaline release in the guinea-pig brain cortex is inhibited via presynaptic H3 receptors and facilitated via H2 receptors not located presynaptically. In the mouse brain cortex, only inhibitory H3 receptors occur. The extent of the H3 receptor-mediated effect is more marked in the mouse than in the guinea-pig brain cortex.

show abstract

The medicinal chemistry and therapeutic potentials of ligands of the histamine H3 receptor

Cited by 35 publications

References 103 publications

H 3 receptor-mediated inhibition of intestinal acetylcholine release: pharmacological characterization of signal transduction pathways

H 3 receptor-mediated inhibition of intestinal acetylcholine release: pharmacological characterization of signal transduction pathways

Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H3 histamine receptors

H2 receptor-mediated facilitation and H3 receptor-mediated inhibition of noradrenaline release in the guinea-pig brain

Contact Info

Product

Resources

About