Vol. 295, Issue 1, 219-225, October 2000

Anti-Inflammatory and Antinociceptive Properties of BP 2-94, a Histamine H₃-Receptor Agonist Prodrug

Agnès Rouleau, Holger Stark, Walter Schunack and Jean-Charles Schwartz

Unité de Neurobiologie et Pharmacologie Moléculaire (U.109) de l'Institut National de la Santé et de la Recherche Médicale, Centre Paul Broca, Paris, France (A.R., J.-C.S.); and Institut für Pharmazie, Freie Universität Berlin, Berlin, Germany (H.S., W.S.)

BP 2-94 is an azomethine prodrug of (R)--methylhistamine [(R)--MeHA], a potent and selective histamine H₃-receptor agonist. When administered orally to mice BP 2-94 was distributed to various peripheral tissues where it released the active drug. BP 2-94 displayed anti-inflammatory and antinociceptive properties in mice. It dose-dependently inhibited carrageenan-induced paw edema with an ED₅₀ value of 0.17 ± 0.05 µmol/kg (p.o.) and a maximal effect of 47%. It also reduced Freund's complete adjuvant-induced paw edema in preventive as well as in curative fashion. Repeated oral administrations of BP 2-94 reduced the pre-established Freund's complete adjuvant-induced edema with an ED₅₀ value of 5 ± 2 µmol/kg (p.o.) and a maximal effect of 47%. The antiedema effects of BP 2-94 and indomethacin were additive. BP 2-94 was also efficient in reducing cyclophosphamide-induced cystitis in mice: it decreased leukocyte infiltration by 62% and plasma protein extravasation by 73% in urinary bladder. In addition, BP 2-94 displayed antinociceptive activity in the capsaicin-induced licking test via H₃-receptor stimulation. Its antinociceptive effect was dose dependent, occurring with an ED₅₀ value of 0.4 ± 0.1 µmol/kg (p.o.) and a maximal reduction of licking duration by 69%. No tolerance to the antinociceptive effect was observed after repeated administration of BP 2-94 for 3 days. These observations with BP 2-94 suggest that H₃-receptor agonists might represent a novel class of anti-inflammatory and antinociceptive agents.