CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H 3 receptor (H 3 R) 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) H 3 R radioligand binding assays was demonstrated. Potent functional antagonism (K b = 0.3 ± 0.1 nM) and inverse agonism (EC 50 = 0.6 ± 0.2 nM) were demonstrated in [35S]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 H 3 R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED 50 = 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 (ED 50 = 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’.