Neurochemical and Behavioral Effects of Ciproxifan, A Potent Histamine H3-Receptor Antagonist

  1. X. Ligneau1,6,
  2. J.-S. Lin2,
  3. G. Vanni-Mercier2,
  4. M. Jouvet2,
  5. J. L. Muir3,
  6. C. R. Ganellin4,
  7. H. Stark5,
  8. S. Elz5,
  9. W. Schunack5 and
  10. J.-C. Schwartz1
  1. 1Unité 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;2Département 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;3School of Psychology, University of Wales, College of Cardiff (J.L.M.), Cardiff CF1 3XR, U.K.; 4Department of Chemistry, University College London (C.R.G.), 20 Gordon Street, London WC1H OAJ, U.K.; 5Freie Universität Berlin, Institut für Pharmazie (H.S., S.E., W.S.), Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany and6Bioprojet (X.L.), 9 rue Rameau, 75002 Paris, France

    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

    • 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.

    • 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.
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    1. JPET November 1, 1998 vol. 287 no. 2 658-666
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