Journal article
CEP-26401 (Irdabisant), a Potent and Selective Histamine H-3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities
The Journal of pharmacology and experimental therapeutics, v 340(1), pp 124-133
01 Jan 2012
PMID: 22001260
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (K-i = 2.7 +/- 0.3 nM) and recombinant rat and human H3R-expressing systems (K-i = 7.2 +/- 0.4 and 2.0 +/- 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [S-35]guanosine 5'-O-(gamma-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 = 0.1 +/- 0.003 mg/kg), and antagonism of the H3R agonist R-alpha-methylhistamine-induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 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 H3R 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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Details
- Title
- CEP-26401 (Irdabisant), a Potent and Selective Histamine H-3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities
- Creators
- Rita Raddatz - Cephalon Inc, Discovery Res, W Chester, PA 19380 USARobert L. Hudkins - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAJoanne R. Mathiasen - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAJohn A. Gruner - Cephalon Inc, Discovery Res, W Chester, PA 19380 USADorothy G. Flood - Cephalon Inc, Discovery Res, W Chester, PA 19380 USALisa D. Aimone - Cephalon Inc, Discovery Res, W Chester, PA 19380 USASiyuan Le - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAHerve Schaffhauser - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAEmir Duzic - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAMaciej Gasior - Cephalon Inc, Discovery Res, W Chester, PA 19380 USADonna Bozyczko-Coyne - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAMichael J. Marino - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAMark A. Ator - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAEdward R. Bacon - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAJohn P. Mallamo - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAMichael Williams - Cephalon Inc, Discovery Res, W Chester, PA 19380 USA
- Publication Details
- The Journal of pharmacology and experimental therapeutics, v 340(1), pp 124-133
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 10
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000298408600014
- Scopus ID
- 2-s2.0-84055219283
- Other Identifier
- 991021900016304721
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- Web of Science research areas
- Pharmacology & Pharmacy