PT  - JOURNAL ARTICLE
AU  - Ligneau, X.
AU  - Lin, J.-S.
AU  - Vanni-Mercier, G.
AU  - Jouvet, M.
AU  - Muir, J. L.
AU  - Ganellin, C. R.
AU  - Stark, H.
AU  - Elz, S.
AU  - Schunack, W.
AU  - Schwartz, J.-C.
TI  - Neurochemical and Behavioral Effects of Ciproxifan, A Potent Histamine H<sub>3</sub>-Receptor Antagonist
DP  - 1998 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 658--666
VI  - 287
IP  - 2
4099  - http://jpet.aspetjournals.org/content/287/2/658.short
4100  - http://jpet.aspetjournals.org/content/287/2/658.full
SO  - J Pharmacol Exp Ther1998 Nov 01; 287
AB  - 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 Ki 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. The American Society for Pharmacology and Experimental Therapeutics