EFFECT OF SEVERAL BICYCLIC PEPTIDE AND CYCLIC PSEUDOPEPTIDE TACHYKININ NK2 RECEPTOR ANTAGONISTS IN THE HUMAN ISOLATED URINARY-BLADDER

1 We have studied several tachykinin NK2 receptor antagonists, bearing a monocyclic pseudopeptide (MEN 10,508, MEN 10,573, MEN 10,581, MEN 1 0,612, MEN 10,619 and MEN 10,677), or bicyclic peptide (MEN 10,627, ME N 10,692, MEN 10,771, MEN 10,882 and MEN 10,993) structure, on the hum an isolated urinary bladder detrusor muscle against neurokinin A as an agonist, and compared their affinities in this preparation with those for NK2 receptors expressed in the rabbit isolated pulmonary artery a nd hamster isolated trachea. 2 In the human bladder, all the antagonis ts tested produced a concentration-dependent and competitive antagonis m of neurokinin A-mediated contractions: among the cyclic pseudopeptid es MEN 10,677 (pK(B) = 8.0) was the most potent antagonist, while amon g the bicyclic analogues it was MEN 10,993 (pK(B) = 8.8). 3 In general , the bicyclic peptide antagonists tested were more potent than the mo nocyclic pseudopeptide compounds, either in the human urinary bladder or in the rabbit pulmonary artery or hamster trachea, showing a nanomo lar affinity for the human NK2 receptor. 4 A highly significant correl ation was found between the estimated pK(B) values of all the antagoni sts tested in the human urinary bladder and rabbit pulmonary artery (r (2) = 0.94, n = 12, P < 0.01), whereas no linear correlation was found between pK(B) values measured in the human urinary bladder and hamste r trachea (r(2) = 0.52, n = 12, P > 0.05): these observations provide further pharmacological evidence for receptor homology between the hum an and rabbit NK2 receptor. 5 The present results point out the class of NK2 receptor antagonists bearing a bicyclic peptide structure, like MEN 10,627, as candidates for testing in pathological conditions, suc h as bladder hyperactivity, for which preclinical evidence indicates t hat a therapeutic effect could result from the block of the tachykinin NK2 receptor.