Anti-Inflammatory and Antinociceptive Properties of BP 2-94, a Histamine H_3-Receptor Agonist Prodrug

摘要

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-inhibited carrageenaninduced paw edema with an ED_(50)value of 0.17 +- 0.05 #mu#mol/kg 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-in-duced edema with an EC_(50) value of 5+-2#mu#mol/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 infitration by 62% and pasma 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 does dependent, occurring with an ED_(50) value of 0.4 +- 0.1 #mu#mol/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 repressent a novel class of anti-inflammatory and antinociceptive agents.