NEUROCHEMICAL AND BEHAVIORAL-EFFECTS OF CIPROXIFAN, A POTENT HISTAMINE H-3-RECEPTOR ANTAGONIST

Ciproxifan, i.e., cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy) phenyl ) ketone, belongs to a novel chemical series of histamine H-3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H-3 autoreceptor controlling [H-3]histamine release from synaptosomes and displayed similar K-i values (0.5-1.9 nM) at the H-3 receptor cont rolling the electrically-induced contraction of guinea pig ileum or at the brain H-3 receptor labeled with [I-125]iodoproxyfan. Ciproxifan d isplayed at least 3-orders of magnitude lower potency at various amine rgic receptors studied in functional or binding tests. In vivo, measur ement of drug plasma levels, using a novel radioreceptor assay in mice receiving ciproxifan p.o. or i.v., led to an oral bioavailability rat io of 62%. Oral administration of ciproxifan to mice enhanced by simil ar to 100% histamine turnover rate and steady state level of tele-meth ylhistamine with an ED50 of 0.14 mg/kg. Ciproxifan reversed the H-3-re ceptor agonist induced enhancement of water consumption in rats with a nd 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 activ ation manifested by enhanced fast-rhythms density and an almost total waking state. In rats, ciproxifan enhanced attention as evaluated in t he five-choice task performed using a short stimulus duration. Ciproxi fan appears to be an orally bioavailable, extremely potent and selecti ve H-3-receptor antagonist whose vigilance- and attention-promoting ef fects are promising for therapeutic applications in aging disorders.