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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Bioavailability, Antinociceptive and Antiinflammatory Properties of BP 2-94, a Histamine H3 Receptor Agonist Prodrug

A. Rouleau, M. Garbarg, X. Ligneau, C. Mantion, P. Lavie, C. Advenier, J.-M. Lecomte, M. Krause, H. Stark, W. Schunack and J.-C. Schwartz
Journal of Pharmacology and Experimental Therapeutics June 1997, 281 (3) 1085-1094;
A. Rouleau
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M. Garbarg
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X. Ligneau
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C. Mantion
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P. Lavie
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C. Advenier
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J.-M. Lecomte
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M. Krause
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H. Stark
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W. Schunack
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J.-C. Schwartz
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Abstract

(R)α-Methylhistamine [(R)α-MeHA], a potent and selective histamine H3 receptor agonistin vitro and in vivo in rodents, was found to display comparatively low plasma level in healthy human volunteers, attributable to an extensive methylation of the drug’s imidazole ring by histamine-N-methyltransferase. To limit this inactivation process, BP 2-94, i.e., (R)-(-)-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino]phenylmethyl] phenol, was selected as a prodrug. A sensitive radioimmunoassay was developed to study the generation of (R)α-MeHA slowly released from BP 2-94 in vitro and in vivo by chemical hydrolysis. In mice after oral administration of BP 2-94 high levels of both prodrug and (R)α-MeHA were detected in plasma and various tissues except in the brain. In humans receiving 0.1 mmol BP 2-94 orally, plasma levels of(R)α-MeHA-like immunoreactivity decayed with at1/2 more than 24 hr, the area under the curve being two orders of magnitude higher than after oral administration of (R)α-MeHA. BP 2-94 displayed antiinflammatory and antinociceptive properties in rodents, related to the H3receptor stimulation. It dose-dependently inhibited capsaicin-induced plasma protein extravasation in many rat tissues with ED50s of 0.6 to 14 μmol/kg p.o., and maximal reductions by 35 to 87%. BP 2-94 also reduced zymosan-induced paw swelling in mice with an ED50 of 1 μmol/kg p.o. and showed marked activity in the phenylbenzoquinone-induced writhing (ED50 = 0.03 μmol/kg, p.o.) or formalin tests in mice, but not in the hot plate jump test. From its pharmacokinetics and pharmacological profile BP 2-94 appears to be a promising novel therapeutic agent in disorders such as asthma, migraine or a variety of inflammatory diseases and pain associated with these disorders.

Footnotes

  • Send reprint requests to: Dr. Jean-Charles Schwartz, Unité de Neurobiologie et Pharmacologie (U.109) de l’INSERM, Centre Paul Broca, 2ter rue d’Alésia, 75014 Paris, France.

  • ↵1 This work was supported by the Biomedical and Health Research Programm EEC BMH1CT92-1087.

  • Abbreviations:
    (R)α-MeHA
    (R)α-methylhistamine
    HA
    histamine
    t-MeHA
    N-tele-methylhistamine
    t-(R)α-diMeHA
    N-tele-(R)α-dimethylhistamine
    Nα
    Nα-diMeHA, Nα, Nα-dimethylhistamine
    α
    α-diMeHA, α, α-dimethylhistamine
    Nα-MeHA
    Nα-methylhistamine
    2-MeHA
    2-methylhistamine
    4-MeHA
    4-methylhistamine
    2-OH-BZP
    2-hydroxybenzophenone
    HMT
    histamine-N-methyltransferase
    PQ
    phenylbenzoquinone
    BZQ
    benzoquinone
    BSA
    bovine serum albumin
    DMSO
    dimethyl sulfoxide
    FITC
    fluorescein isothiocyanate
    A.U.C.
    area under the curve
    RIA
    radioimmunoassay
    REA
    radioenzymatic assay
    ir
    immunoreactivity
    CGRP
    calcitonin-gene-related peptide
    • Received March 26, 1996.
    • Accepted February 19, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 3
1 Jun 1997
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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Bioavailability, Antinociceptive and Antiinflammatory Properties of BP 2-94, a Histamine H3 Receptor Agonist Prodrug

A. Rouleau, M. Garbarg, X. Ligneau, C. Mantion, P. Lavie, C. Advenier, J.-M. Lecomte, M. Krause, H. Stark, W. Schunack and J.-C. Schwartz
Journal of Pharmacology and Experimental Therapeutics June 1, 1997, 281 (3) 1085-1094;

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OtherPROSTAGLANDINS, LEUKOTRIENES AND OTHER EICOSANOIDS

Bioavailability, Antinociceptive and Antiinflammatory Properties of BP 2-94, a Histamine H3 Receptor Agonist Prodrug

A. Rouleau, M. Garbarg, X. Ligneau, C. Mantion, P. Lavie, C. Advenier, J.-M. Lecomte, M. Krause, H. Stark, W. Schunack and J.-C. Schwartz
Journal of Pharmacology and Experimental Therapeutics June 1, 1997, 281 (3) 1085-1094;
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