title: CEP-26401 (irdabisant), a potent and selective histamine H₃ 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 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 (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 [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.
authors: Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rraddatz@cephalon.com
authors: Rita
authors: R
authors: Raddatz
authors: Robert L
authors: RL
authors: Hudkins
authors: Joanne R
authors: JR
authors: Mathiasen
authors: John A
authors: JA
authors: Gruner
authors: Dorothy G
authors: DG
authors: Flood
authors: Lisa D
authors: LD
authors: Aimone
authors: Siyuan
authors: S
authors: Le
authors: Hervé
authors: H
authors: Schaffhauser
authors: Emir
authors: E
authors: Duzic
authors: Maciej
authors: M
authors: Gasior
authors: Donna
authors: D
authors: Bozyczko-Coyne
authors: Michael J
authors: MJ
authors: Marino
authors: Mark A
authors: MA
authors: Ator
authors: Edward R
authors: ER
authors: Bacon
authors: John P
authors: JP
authors: Mallamo
authors: Michael
authors: M
authors: Williams
mesh_terms: D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D018697:Nootropic Agents; D011724:Pyridazines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D012919:Social Behavior; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D018076:DNA, Complementary; D054828:Histamine H3 Antagonists; D018697:Nootropic Agents; D011724:Pyridazines; D011759:Pyrrolidines; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C561238:6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one