Anti-inflammatory and antinociceptive properties of BP 2-94, a histamine H(3)-receptor agonist prodrug.

BP 2-94 is an azomethine prodrug of (R)-alpha-methylhistamine [(R)-alpha-MeHA], a potent and selective histamine H(3)-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 ED(50) value of 0.17 +/- 0.05 micromol/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 ED(50) value of 5 +/- 2 micromol/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 H(3)-receptor stimulation. Its antinociceptive effect was dose dependent, occurring with an ED(50) value of 0.4 +/- 0.1 micromol/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 H(3)-receptor agonists might represent a novel class of anti-inflammatory and antinociceptive agents.