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Vol. 287, Issue 2, 658-666, November 1998
Unité de Neurobiologie et Pharmacologie
Moléculaire (U. 109) de I'INSERM, Centre Paul Broca (X.L.,
J.-C.S.), 2ter rue d'Alésia, 75014 Paris, France;
Département de Médecine Expérimentale (U. 52) de
I'INSERM, CNRS URA 1195, Université Claude Bernard (J.-S.L.,
G.V.-M., M.J.), 8 avenue Rockefeller, 69373 Lyon Cedex 2, France;
School of Psychology, University of Wales, College of Cardiff (J.L.M.),
Cardiff CF1 3XR, U.K.;
Department of Chemistry, University College
London (C.R.G.), 20 Gordon Street, London WC1H OAJ, U.K.;
Freie
Universität Berlin, Institut für Pharmazie (H.S., S.E.,
W.S.), Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany and
Bioprojet (X.L.), 9 rue Rameau, 75002 Paris, France
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 of
tele-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.
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