CEP-26401 (Irdabisant), a potent and selective histamine H 3 receptor antagonist/inverse agonist with cognition-enhancing and wake-promoting activities

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 (H 3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H 3R was demonstrated in radioligand binding displacement assays in rat brain membranes (K i = 2.7 ± 0.3 nM) and recombinant rat and human H 3R-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 [ 35S]guanosine 5′-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H 3R 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 3R agonist R-α-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 3R 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. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics.