title: Anti-inflammatory and antinociceptive properties of BP 2-94, a histamine H(3)-receptor agonist prodrug.
abstract: 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.
authors.affiliation: 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. rouleau@broca.inserm.fr
authors.forename: A
authors.initials: A
authors.lastname: Rouleau
authors.forename: H
authors.initials: H
authors.lastname: Stark
authors.forename: W
authors.initials: W
authors.lastname: Schunack
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003556:Cystitis / Q000188:drug therapy; D004487:Edema / Q000188:drug therapy; D017442:Histamine Agonists / Q000494:pharmacology*; D007097:Imines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000187:drug effects*
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017442:Histamine Agonists; D007097:Imines; D008761:Methylhistamines; D010636:Phenols; D011355:Prodrugs; D018100:Receptors, Histamine H3; C106714:BP 2-94; C069357:alpha-methylhistamine