Histamine H3 receptor-mediated modulation of water consumption in the rat

Clapham, Jane; Kilpatrick, Gavin J.

doi:10.1016/0014-2999(93)90733-x

Cited by 64 publications

(26 citation statements)

References 11 publications

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“…The H 3 R-selective agonist RAMH induces increased water intake that can be blocked by the administration of H 3 R antagonists (Clapham and Kilpatrick, 1993;Fox et al, 2002). The dipsogenic effect is produced after intraperitoneal or intracerebroventricular administration of RAMH, indicating interaction with central H 3 Rs (Lecklin et al, 1998) (Fig.…”

Section: Resultsmentioning

confidence: 98%

CEP-26401 (Irdabisant), a Potent and Selective Histamine H₃ Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

Raddatz¹,

Hudkins²,

Mathiasen³

et al. 2011

J Pharmacol Exp Ther

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CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H 3 receptor (H 3 R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H 3 R was demonstrated in radioligand binding displacement assays in rat brain membranes (K i ϭ 2.7 Ϯ 0.3 nM) and recombinant rat and human H 3 R-expressing systems (K i ϭ 7.2 Ϯ 0.4 and 2.0 Ϯ 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [35 S]guanosine 5Ј-O-(␥-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H 3 R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC 50 ϭ 0.1 Ϯ 0.003 mg/kg), and antagonism of the H 3 R agonist R-␣-methylhistamine-induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED 50 ϭ 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H 3 R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.

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Section: Resultsmentioning

confidence: 98%

CEP-26401 (Irdabisant), a Potent and Selective Histamine H₃ Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

Raddatz¹,

Hudkins²,

Mathiasen³

et al. 2011

J Pharmacol Exp Ther

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“…(R)-a-Methylhistamine does have significant H 4 receptor activity (binding pK i of 6.85, human H 4 receptor in transfected cells) (Liu et al, 2001a,b;Morse et al, 2001) and pK i = 6.1 at rat H 4 receptor. This agonist also induces water drinking in rodents, a finding used as the basis of an in vivo pharmacological model (Clapham and Kilpatrick, 1993;Ligneau et al, 1998;Fox et al, 2002). Prodrugs of (R)-a-methylhistamine have been described with an improved pharmacokinetic profile (Krause et al, 2001;Stark et al, 2001).…”

Section: E H 3 -Selective Ligandsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

et al. 2015

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“…The effect of GSK189254 on H 3 receptor agonist-induced water intake in male Lister Hooded rats (370 -500 g; Harlan UK Limited, Bicester, Oxon, UK) was tested in a dipsogenia model similar to that described previously (Clapham and Kilpatrick, 1993). Groups of individually housed rats with access to water via identical bottles and spouts received either vehicle (1% aqueous methylcellulose; n ϭ 6) or GSK189254 (0.01-0.3 mg/kg p.o.…”

Section: Downloaded Frommentioning

confidence: 99%

GSK189254, a Novel H₃Receptor Antagonist That Binds to Histamine H₃Receptors in Alzheimer's Disease Brain and Improves Cognitive Performance in Preclinical Models

Medhurst

Atkins²,

Beresford³

et al. 2007

J Pharmacol Exp Ther

288

234

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6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H 3 receptor antagonist with high affinity for human (pK i ϭ 9.59 -9.90) and rat (pK i ϭ 8.51-9.17) H 3 receptors. GSK189254 is Ͼ10,000-fold selective for human H 3 receptors versus other targets tested, and it exhibited potent functional antagonism (pA 2 ϭ 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC 50 Progressive decline in cognitive performance is a key characteristic of Alzheimer's disease (AD) and related dementias, and improving cognitive function in these diseases represents a complex challenge, given the involvement of numerous neurotransmitter systems and brain regions (CoreyBloom, 2002). Current therapies, such as cholinesterase inhibitors, provide only minimal benefit to a subset of patients and for a limited period, so a number of alternative Article, publication date, and citation information can be found at

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Histamine H3 receptor-mediated modulation of water consumption in the rat

Cited by 64 publications

References 11 publications

CEP-26401 (Irdabisant), a Potent and Selective Histamine H₃ Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

CEP-26401 (Irdabisant), a Potent and Selective Histamine H₃ Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

GSK189254, a Novel H₃Receptor Antagonist That Binds to Histamine H₃Receptors in Alzheimer's Disease Brain and Improves Cognitive Performance in Preclinical Models

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Histamine H3 receptor-mediated modulation of water consumption in the rat

Cited by 64 publications

References 11 publications

CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

GSK189254, a Novel H3Receptor Antagonist That Binds to Histamine H3Receptors in Alzheimer's Disease Brain and Improves Cognitive Performance in Preclinical Models

Contact Info

Product

Resources

About

CEP-26401 (Irdabisant), a Potent and Selective Histamine H₃ Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

CEP-26401 (Irdabisant), a Potent and Selective Histamine H₃ Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

GSK189254, a Novel H₃Receptor Antagonist That Binds to Histamine H₃Receptors in Alzheimer's Disease Brain and Improves Cognitive Performance in Preclinical Models