a link of potential interest......
exchange2000.com
And, parking this...... sorry if I've posted it before.....
J Pharmacol Exp Ther 1998 Nov;287(2):658-66
Neurochemical and behavioral effects of ciproxifan, a potent histamine
H3-receptor antagonist.
Ligneau X, Lin J, Vanni-Mercier G, Jouvet M, Muir JL, Ganellin CR, Stark H, Elz S, Schunack W, Schwartz J
Unite de Neurobiologie et Pharmacologie Moleculaire (U. 109) de I'INSERM, Centre Paul Broca, 2ter rue d'Alesia, 75014
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 approximately 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. |
