Antioedematogenic and antinociceptive actions of NPC 18521, a novel bradykinin B2 receptor antagonist.

The novel pseudopeptide bradykinin B2 receptor antagonist containing the 1,3,8-triazaspiro[4,5]decan-4-one ring system, NPC 18521 (D-Arg-Arg-[1,3-phenyl,8-triazaspiro[4,5]-decane-4-one-3-acetyl]-S er-D -tetrahydroisoquinolinyl-octahydroindolinyl-Arg) (10 and 30 nmol/kg, i.p.), given 30 min prior, produced significant and long-lasting inhibition of rat paw oedema induced by bradykinin (3 nmol/paw) and carrageenan (300 micrograms/paw), without affecting the oedema induced by the selective bradykinin B1 receptor agonist, des-Arg9-bradykinin, in rats pretreated with Escherichia coli endotoxin. In contrast, when injected locally into the rat or mouse hindpaw, NPC 18521 (1-100 nmol) elicited dose-related oedema formation. This effect was almost completely blocked by cyproheptadine (20 mg/kg, i.p.) or by compound 48/80 (12 micrograms/paw), but was unaffected by Hoe 140 (D-Arg-[Hyp5,Thi5,Tic7,Oic8]bradykinin). NPC 18521 (0.3-10 nmol/kg, i.p.) produced significant inhibition of acetic acid, acetylcholine and kaolin- but not zymosan-induced abdominal constrictions in mice. The calculated mean ID50 values for these effects were 0.84, 0.46 and 0.55 nmol/kg, respectively. The antinociceptive 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 18521 produced significant attenuation of both the early and the late phase of the formalin-induced licking, as well as formalin-induced oedema formation. In addition, NPC 18521 given both systemically or topically, produced significant inhibition of the neurogenic nociception caused by topical injection of capsaicin. Given topically in the rat paw, NPC 18521 (10 nmol) caused marked hyperalgesia, an effect which was completely prevented by cyproheptadine (20 mg/kg, i.p.), but was unaffected by Hoe 140 (3 nmol/kg, i.p.). Given intraperitoneally, 30 min prior, 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 B2 receptor antagonist, NPC 18521, has an effect with rapid onset, and produces potent and relatively long-lasting antioedematogenic and antinociceptive properties. However, in contrast to Hoe 140, given locally into the hindpaw, NPC 18521 elicited marked oedema formation and hyperalgesia, an effect which seems to be secondary to mast cell degranulation and histamine and/or serotonin release. Finally, the anti-bradykinin actions of NPC 18521 are quite selective towards the bradykinin B2 receptor-mediated responses.