PT  - JOURNAL ARTICLE
AU  - Raddatz, Rita
AU  - Hudkins, Robert L.
AU  - Mathiasen, Joanne R.
AU  - Gruner, John A.
AU  - Flood, Dorothy G.
AU  - Aimone, Lisa D.
AU  - Le, Siyuan
AU  - Schaffhauser, Hervé
AU  - Duzic, Emir
AU  - Gasior, Maciej
AU  - Bozyczko-Coyne, Donna
AU  - Marino, Michael J.
AU  - Ator, Mark A.
AU  - Bacon, Edward R.
AU  - Mallamo, John P.
AU  - Williams, Michael
TI  - CEP-26401 (Irdabisant), a Potent and Selective Histamine H<sub>3</sub> Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities
AID  - 10.1124/jpet.111.186585
DP  - 2012 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 124--133
VI  - 340
IP  - 1
4099  - http://jpet.aspetjournals.org/content/340/1/124.short
4100  - http://jpet.aspetjournals.org/content/340/1/124.full
SO  - J Pharmacol Exp Ther2012 Jan 01; 340
AB  - CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 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 (Ki = 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (Ki = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [35S]guanosine 5′-O-(γ-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-α-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.