Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist.
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.
Ligneau
X
X
Unité de Neurobiologie et Pharmacologie Moléculaire (U. 109) de I'INSERM, Centre Paul Broca, 2ter rue d'Alésia, 75014 Paris, France.
Lin
J
J
Vanni-Mercier
G
G
Jouvet
M
M
Muir
J L
JL
Ganellin
C R
CR
Stark
H
H
Elz
S
S
Schunack
W
W
Schwartz
J
J
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002415:Cats; D004569:Electroencephalography; D005260:Female; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D008297:Male; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism
D006633:Histamine Antagonists; D007093:Imidazoles; D007457:Iodine Radioisotopes; D008761:Methylhistamines; D018100:Receptors, Histamine H3; C090115:iodoproxyfan; C115705:ciproxifan; C020404:tele-methylhistamine