MEN-10,573 AND MEN-10,612, NOVEL CYCLIC PSEUDOPEPTIDES WHICH ARE POTENT TACHYKININ NK-2 RECEPTOR ANTAGONISTS

The activity and selectivity of MEN 10,573 and MEN 10,612, novel cycli c pseudopeptides which are selective tachykinin NK-2 receptor antagoni sts is described, as compared to that of previously characterized line ar and cyclic compounds. For the NK-2 receptor, the activity of test c ompounds was investigated in the hamster isolated trachea (HT) and the endothelium-deprived rabbit isolated pulmonary artery (RPA), two prep arations which are endowed with pharmacologically distinct forms of th e NK-2 receptor. The novel cyclic pseudopeptides, MEN 10,573 and MEN 1 0,612 displayed very high affinity for the NK-2 receptor in the HT (pA 2 8.66 and 9.06, respectively) which is higher than that observed in t he RPA (pA2 7.31 and 7.41 for MEN 10,573 and MEN 10,612, respectively) . The antagonism exerted by MEN 10,573 and MEN 10,612 was of competiti ve nature in both preparations. MEN 10,573 and MEN 10,612 also display ed competitive antagonism for NK-2 receptor-mediated responses in the rabbit bronchus (RB), rat vas deferens (RVD), circular muscle of the h uman colon (HUC) and ileum (HUI). In the RB, HUC and HUI, the potency of the novel cyclic pseudopeptides was comparable to that of MDL 29,91 3 and about 10-fold greater than that of L659,877. In the RVD however, the potency of MEN 10,573 MEN 10,612 or MDL 29,913 was similar to tha t of L659,877. In anaesthetized rats, i.v. injection of MEN 10,612 pro duced a selective and long-lasting blockade of the urinary bladder con traction produced by the i.v. injection of the NK-2 receptor selective agonist [betaAla8]neurokinin A(4-10), without affecting the response to the NK-1 receptor selective agonist [Sar9]substance P sulfone. Dura tion of NK-2 receptor blockade by MEN 10,612 in vivo was greater than that produced by MDL 29,913 or L659,877. We conclude that MEN 10,573 a nd MEN 10,612 are novel potent antagonists of the tachykinin NK-2 rece ptor, suitable for both in vitro and in vivo investigations of the bio logical role of tachykinins. The potency at NK-2 receptors from variou s species indicate that these novel pseudopeptides are the most potent ligands available for blocking the previously characterized NK-2B rec eptor.