Abstract

Ciproxifan, i.e., cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy) phenyl) ketone, belongs to a novel chemical series of histamine H₃-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H₃ autoreceptor controlling [³H]histamine release from synaptosomes and displayed similar K_i values (0.5–1.9 nM) at the H₃ receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H₃ receptor labeled with [¹²⁵I]iodoproxyfan. Ciproxifan displayed at least 3-orders of magnitude lower potency at various aminergic receptors studied in functional or binding tests. In vivo, measurement of drug plasma levels, using a novel radioreceptor assay in mice receiving ciproxifan p.o. or i.v., led to an oral bioavailability ratio of 62%. Oral administration of ciproxifan to mice enhanced by ∼100% histamine turnover rate and steady state level oftele-methylhistamine with an ED₅₀ of 0.14 mg/kg. Ciproxifan reversed the H₃-receptor agonist induced enhancement of water consumption in rats with and ID₅₀ of 0.09 ± 0.04 mg/kg, i.p. In cats, ciproxifan (0.15–2 mg/kg, p.o.) induced marked signs of neocortical electroencephalogram activation manifested by enhanced fast-rhythms density and an almost total waking state. In rats, ciproxifan enhanced attention as evaluated in the five-choice task performed using a short stimulus duration. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H₃-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.