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

被引:53
作者
Raddatz, Rita [1 ]
Hudkins, Robert L. [1 ]
Mathiasen, Joanne R. [1 ]
Gruner, John A. [1 ]
Flood, Dorothy G. [1 ]
Aimone, Lisa D. [1 ]
Le, Siyuan [1 ]
Schaffhauser, Herve [1 ]
Duzic, Emir [1 ]
Gasior, Maciej [1 ]
Bozyczko-Coyne, Donna [1 ]
Marino, Michael J. [1 ]
Ator, Mark A. [1 ]
Bacon, Edward R. [1 ]
Mallamo, John P. [1 ]
Williams, Michael [1 ]
机构
[1] Cephalon Inc, Discovery Res, W Chester, PA 19380 USA
关键词
PHARMACOLOGICAL-PROPERTIES; CONSTITUTIVE ACTIVITY; PREPULSE INHIBITION; INVERSE AGONIST; SOCIAL MEMORY; H-3-RECEPTOR; BRAIN; TARGET; IDENTIFICATION; MODULATION;
D O I
10.1124/jpet.111.186585
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:124 / 133
页数:10
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