Pharmacological activity of VUF 9153, an isothiourea histamine H3 receptor antagonist

Barnes, Julie C.; Brown, Jason; Clarke, Nicholas; Clapham, Jane; Evans, Deborah; O’Shaughnessy, Celestine T.

doi:10.1016/0014-2999(93)90632-r

Cited by 43 publications

(19 citation statements)

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“…The electrically evoked tritium overflow in this preparation represents quasi-physiological noradrenaline release (Schlicker et al 1992b) and is inhibited by histamine via H 3 receptors (possibly H3A; Schlicker et al t992a). Only the highest concentration of clozapine (50 gM) produced a slight inhibition of evoked overflow which cannot be attributed to the activation of H 3 receptors, since it was not counteracted by a high concentration of the H 3 receptor antagonist clobenpropit (Van der Goot et al 1992;Barnes et al 1993;Kathmann et al 1993). The inhibitory effect of clozapine 50 gM on the evoked overflow has to be interpreted with caution anyway, since it occurred at a markedly increased basal tritium efflux.…”

Section: Discussionmentioning

confidence: 94%

Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H3 receptors

1994

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It was the aim of the present study to determine the affinities of four neuroleptics and five antidepressants for histamine H3 receptors. In rat brain cortex membranes, the specifically bound [3H]-N alpha-methylhistamine was monophasically displaced by clozapine (pKi 6.15). The other drugs did not completely displace the radioligand even at 100 microM; the pKi values were: haloperidol (4.91); sulpiride (4.73); amitriptyline (4.56); desipramine (4.15); levomepromazine (4.14); fluovoxamine (4.13); maprotiline (4.09); moclobemide (< 4.0). The effect of clozapine was further examined in a functional H3 receptor model, i.e., in superfused mouse brain cortex slices preincubated with [3H]-noradrenaline. The electrically evoked tritium overflow was not affected by clozapine 0.5-32 microM. However, clozapine shifted the concentration-response curve of histamine for its inhibitory effect on the evoked overflow to the right, but did not affect the maximum effect of histamine. The Schild plot yielded a pA2 value of 6.33. In conclusion, clozapine shows an intermediate affinity and potency (as a competitive antagonist) at H3 receptors. The Ki value of clozapine at H3 receptors resembles its Ki value at D2 receptors (the target of the classical neuroleptics), but is higher than its Ki values at D4, 5-HT2 or muscarinic acetylcholine receptors, which according to current hypotheses, might be involved in the atypical profile of clozapine.

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Section: Discussionmentioning

confidence: 94%

Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H3 receptors

1994

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“…The ex vivo receptor binding assay has been useful in examining the ability of compounds to penetrate the blood-brain barrier and to bind receptors (Taylor et al, 1992). This approach has been used in previous reports for assessing the in vivo receptor binding of a variety of compounds, including H 3 R antagonists thioperamide (Barnes et al, 1993;Bertoni et al, 2007), VUF 9153 (Barnes et al, 1993), JNJ-5207852 (Barbier et al, 2004), GSK189254 (Medhurst et al, 2007a), GSK207040, and GSK334429 (Medhurst et al, 2007b). In the present study, the data demonstrate a dose-dependent inhibition of the ex vivo binding by H 3 R antagonists in rat cortical homogenate.…”

Section: Discussionmentioning

confidence: 99%

Correlation between ex Vivo Receptor Occupancy and Wake-Promoting Activity of Selective H₃Receptor Antagonists

Le¹,

Gruner²,

Mathiasen³

et al. 2008

J Pharmacol Exp Ther

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The histamine H 3 receptor (H 3 R) modulates the release of neurotransmitters that are involved in vigilance, cognition, and sleepwake regulation. H 3 R antagonism has been proposed as a novel approach to the treatment of cognitive and attention deficit as well as sleep disorders. It is apparent that H 3 R antagonists produce pharmacological effects in preclinical animal models across a wide dose range. Several H 3 R antagonists were reported to be effective at producing cognitive enhancing effects at low doses, while producing robust wake enhancement at higher doses. To better understand the effect of H 3 R antagonists across a broad dose range, an ex vivo receptor binding assay has been used to estimate the degree of H 3 R occupancy in vivo. The H 3 R antagonists ciproxifan, thioperamide, GSK189254 (6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride), and ABT-239produced wake-promoting activity in vivo and a dose-dependent inhibition of H 3 R binding ex vivo. For ciproxifan, thioperamide, and GSK189254, a relatively low level of cumulative wake activity was linearly correlated with up to 80% of the receptor occupancy. In contrast, an abrupt break from linearity and a robust increase of waking activity was observed at doses that produce greater than 80% occupancy. Our results suggest a relatively small increase of waking activity at low levels of receptor occupancy that may be consistent with reported enhancement of attention and cognitive function. Robust waking activity at higher levels of H 3 R occupancy may be mechanistically different from activities at low levels of H 3 R occupancy.The neurotransmitter histamine is synthesized by neurons originating in the tuberomammillary nucleus of the posterior hypothalamus. These neurons project widely throughout the cortex, hippocampus, amygdala, and striatum (Brown et al., 2001). Histamine exerts its action by interacting with a group of G protein-coupled histamine receptors and plays important roles in mediating a variety of functions in the central nervous system (Brown et al., 2001). The H 3 R is presynaptically localized and functions both as an autoreceptor and a heteroreceptor by modulating the release of neurotransmitters, including histamine (Arrang et al., 1985), dopamine, acetylcholine, serotonin, and norepinephrine (Schlicker et al., 1994;Blandina et al., 1996;Brown et al., 2001). Activation of the H 3 R results in the inhibition of neurotransmitter release. In contrast, blockade of the H 3 R by selective antagonists or inverse agonists can reverse the histamine-mediated inhibition of neurotransmitter release. By virtue of the unique central nervous system localization of the H 3 R (Drutel et al., 2001;Leurs et al., 2005) and its ability to regulate a variety of neurotransmitters that are thought to be involved in vigilance, cognition, and wakefulness, H 3 R antagonists and inverse agonists are suggested to hold promise for a number of therapeutic applications (Hancock and Fox, 2004).Selectiv...

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“…First, imidazole-based H 3 R antagonists such as thioperamide (Arrang et al, 1987), ciproxifan (Ligneau et al, 1998), clobenpropit (Barnes et al, 1993), and cipralisant (Tedford et al, 1998) were made, and although they were useful pharmacological tools, they suffered pharmacokinetic and metabolic issues that halted their development as human therapeutics (Esbenshade et al, 2008). More recently, novel selective nonimidazole H 3 R antagonists (Esbenshade et al, 2008;Celanire et al, 2009;Leurs et al, 2011), including pitolisant [1- (3-(3-(4-chlorophenyl) propoxy)propyl)piperidine (BF2.649)], 6-( (3-cyclobutyl-2,3,4, 5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide (GSK189254), 5-((3-cyclobutyl-2,3,4, 5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-2-pyrazinecarboxamide (GSK207040), 2-methyl-3-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-5-trifluoromethyl-3H-quinazolin-4-one (MK-0249), 1-{3-[4-(piperidin-1-ylmethyl)phenoxy]propyl}pi-peridine (JNJ-17216498), and irdabisant [6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one (CEP-26401)] have been advanced to early human trials for a variety of indications.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H₃Receptor Antagonist

Esbenshade

Browman

Miller

et al. 2012

J Pharmacol Exp Ther

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Pharmacological activity of VUF 9153, an isothiourea histamine H3 receptor antagonist

Cited by 43 publications

References 10 publications

Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H3 receptors

Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H3 receptors

Correlation between ex Vivo Receptor Occupancy and Wake-Promoting Activity of Selective H₃Receptor Antagonists

Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H₃Receptor Antagonist

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Pharmacological activity of VUF 9153, an isothiourea histamine H3 receptor antagonist

Cited by 43 publications

References 10 publications

Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H3 receptors

Intermediate affinity and potency of clozapine and low affinity of other neuroleptics and of antidepressants at H3 receptors

Correlation between ex Vivo Receptor Occupancy and Wake-Promoting Activity of Selective H3Receptor Antagonists

Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H3Receptor Antagonist

Contact Info

Product

Resources

About

Correlation between ex Vivo Receptor Occupancy and Wake-Promoting Activity of Selective H₃Receptor Antagonists

Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H₃Receptor Antagonist