CEP-26401 (Irdabisant), a Potent and Selective Histamine H(3) Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

[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 (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) = 2.7 +/- 0.3 nM) and recombinant rat and human H(3)R-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 [(35)S]guanosine 5'-O-(gamma-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) = 0.1 +/- 0.003 mg/kg), and antagonism of the H(3)R agonist R-alpha-methylhistamine-induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED(50) = 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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