Abstract
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.
Footnotes
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Send reprint requests to: Dr. Jean-Charles Schwartz, Unité de Neurobiologie et Pharmacologie Moléculaire (U.109), Centre Paul Broca de I’INSERM, 2ter rue d’Alésia, 75014 Paris, France.
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1 This work was supported by the Biomedical and Health Research Program EEC BMH4 CT96-0204 and the Direction des Recherches Etudes et Techniques (DRET 92/045).
- Abbreviations:
- HA
- histamine
- t-MeHA
- tele-methylhistamine
- (R)α-MeHA
- (R)α-methylhistamine
- AUC
- area under the curve
- Cmax
- maximal concentration
- W
- wakefulness
- S1
- light slow wave sleep
- S2
- deep slow wave sleep
- PS
- paradoxical sleep
- EEG
- electroencephalogram
- Received February 24, 1998.
- Accepted June 7, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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