Journal article
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 H-3 antagonist/inverse agonist
Neuropharmacology, v 106, pp 37-45
01 Jul 2016
PMID: 26400408
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H-3 receptor (H3R) with drug-like properties. High affinity in human (hH(3)R K-i = 2.0 +/- 0.2 nM) and rat (rH(3)R K-i = 3.6 +/- 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (K-b = 0.3 +/- 0.1 nM) and inverse agonism (EC30 = 0.6 +/- 0.2 nM) were demonstrated in [S-35]guanosine 5'-O-(gamma-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-alpha-methylhistamine-induced drinking in the rat dipsogenia model (ED30 = 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'. (C) 2015 Elsevier Ltd. All rights reserved.
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Details
- 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 H-3 antagonist/inverse agonist
- Creators
- Robert L. Hudkins - Teva PharmaceuticalsJohn A. Gruner - Teva PharmaceuticalsRita Raddatz - Teva PharmaceuticalsJoanne R. Mathiasen - Teva PharmaceuticalsLisa D. Aimone - Teva PharmaceuticalsMichael J. Marino - Teva PharmaceuticalsEdward R. Bacon - Teva PharmaceuticalsMichael Williams - Teva PharmaceuticalsMark A. Ator - Teva Pharmaceuticals
- Publication Details
- Neuropharmacology, v 106, pp 37-45
- Publisher
- Elsevier
- Number of pages
- 9
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000378964500006
- Scopus ID
- 2-s2.0-84950128002
- Other Identifier
- 991021900194204721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Neurosciences
- Pharmacology & Pharmacy