The nonpeptide B2 receptor antagonist FR173657:: inhibition of effects of bradykinin related to its role in nociception

1 The nonpeptide bradykinin B-2 receptor antagonist, FR173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N(2,4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylaminocarbonylmethyl] acrylamide), was tested in models involving bradykinin-induced activation of primary afferent neurones in vitro and in vivo. 2 Bradykinin-induced contractions of the rabbit isolated iris sphincter muscle mediated by tachykinin release from trigeminal afferent neurones were inhibited in a non-competitive manner by FR173657. A pK(B) value of 7.9 was calculated. Effects of substance P were unaffected by FR173657. 3 Nociceptive behavioural responses following intraplantar injection of bradykinin in unanaesthetized rats were reduced by 0.3 mu mol kg(-1) FR173657 s.c. (P<0.05), and completely abolished by 3 mu mol kg(-1) (P<0.05). Peroral administration of 5 mu mol kg(-1) FR173657 abolished the bradykinin effects (P<0.05); lower doses had no significant effect. 4 Shortening by intraplantar injection of bradykinin of the paw withdrawal latency in response to radiant heat was abolished by 3 mu mol kg(-1) FR173657 s.c. (P<0.05), while 300 nmol kg(-1) had an intermediate effect. Hyperalgesia induced by prostaglandin E-2 remained unaffected by FR173657. 5 Blood pressure reflexes following i.p. instillation of bradykinin in anaesthetized rats were inhibited by FR173657 s.c. with an ID50 of 1.1 mu mol kg(-1), while the peptidic B-2 antagonist icatibant (Hoe-140; D-Arg(0)-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-bradykinin) caused inhibition at significantly lower doses (ID50 8.5 nmol kg(-1) P<0.001). Responses to hydrochloric acid i.p. remained unaffected by FR173657. 6 FR173657 or similar nonpeptide compounds may be useful for the development of drugs for diseases involving pain induced by the release of endogenous kinins, i.e. especially in acute inflammatory conditions.