ANTIOEDEMATOGENIC AND ANTINOCICEPTIVE ACTIONS OF NPC-18521, A NOVEL BRADYKININ B-2 RECEPTOR ANTAGONIST

The novel pseudopeptide bradykinin B-2 receptor antagonist containing the 1,3,8-triazaspiro[4.5]decan-4-one ring system, NPC 18521 -D-tetrah ydroisoquinolinyl-octahydroindolinyl-Arg) (10 and 30 nmol/kg, i.p.), g iven 30 min prior, produced significant and long-lasting inhibition of rat paw oedema induced by bradykinin (3 nmol/paw) and carrageenan (30 0 mu g/paw), without affecting the oedema induced by the selective bra dykinin B-1 receptor agonist, des-Arg(9)-bradykinin, in rats pretreate d with Escherichia coli endotoxin. Tn contrast, when injected locally into the rat or mouse hindpaw, NPC 18521 (1-100 nmol) elicited dose-re lated oedema formation. This effect was almost completely blocked by c yproheptadine (20 mg/kg, i.p.) or by compound 48/80 (12 mu g/paw), but was unaffected by Hoe 140 (D-Arg-[Hyp(5),Thi(5),Tic(7),Oic(8)]bradyki nin). NPC 18521 (0.3-10 nmol/kg, i.p.) produced significant inhibition of acetic acid, acetylcholine and kaolin- but not zymosan-induced abd ominal constrictions in mice. The calculated mean ID50 values for thes e effects were 0.84, 0.46 and 0.55 nmol/kg, respectively. The antinoci ceptive action of NPC 18521 (3 nmol/kg, i.p.) had a rapid onset(15 min ) and lasted for up to 120 min, Given topically (0.01-0.3 nmol), NPC 1 8521 produced significant attenuation of both the early and the late p hase of the formalin-induced licking, as well as formalin-induced oede ma formation. In addition, NPC 18521 given both systemically or topica lly, produced significant inhibition of the neurogenic nociception cau sed by topical injection of capsaicin. Given topically in the rat paw, NPC 18521 (10 nmol) caused marked hyperalgesia, an effect which was c ompletely prevented by cyproheptadine (20 mg/kg, i.p.), but was unaffe cted by Hoe 140 (3 nmol/kg, i.p.). Given intraperitoneally, 30 min pri or, NPC 18521 (3-30 nmol/kg) like Hoe 140 (1-10 nmol/kg) prevented, in a dose-dependent manner, bradykinin (3 nmol/paw)-induced hyperalgesia with mean ID50 values of 13.16 and 1.36 nmol/kg, respectively, Thus, the novel pseudopeptide bradykinin B-2 receptor antagonist, NPC 18521, has an effect with rapid onset, and produces potent and relatively lo ng-lasting antioedematogenic and antinociceptive properties. However, in contrast to Hoe 140, given locally into the hindpaw, NPC 18521 elic ited marked oedema formation and hyperalgesia, an effect which seems t o be secondary to mast cell degranulation and histamine and/or seroton in release. Finally, the anti-bradykinin actions of NPC 18521 are quit e selective towards the bradykinin B-2 receptor-mediated responses.