title: 3-(1'-Cyclobutylspiro[4H-1,3-benzodioxine-2,4'-piperidine]-6-yl)-5,5-dimethyl-1,4-dihydropyridazin-6-one (CEP-32215), a new wake-promoting histamine H3 antagonist/inverse agonist.
abstract: CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. Electronic address: robert.hudkins@tevapharm.com.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Gruner
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marino
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Bacon
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
authors.affiliation: Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004326:Drinking / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D054314:Drug Inverse Agonism; D017442:Histamine Agonists / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D013141:Spiro Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D014851:Wakefulness / Q000187:drug effects* / Q000502:physiology
chemical_list: C000620743:3-(1'-cyclobutylspiro(4H-1,3-benzodioxine-2,4'-piperidine)-6-yl)-5,5-dimethyl-1,4-dihydropyridazin-6-one; D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D008761:Methylhistamines; D010880:Piperidines; D011719:Pyrazines; D018100:Receptors, Histamine H3; D013141:Spiro Compounds; C069357:alpha-methylhistamine
keywords: CEP-32215; H(3)R inverse agonist; Histamine H(3) receptor; Sleep wake activity