title: MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are potent tachykinin NK-2 receptor antagonists.
abstract: The activity and selectivity of MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are selective tachykinin NK-2 receptor antagonists is described, as compared to that of previously characterized linear and cyclic compounds. For the NK-2 receptor, the activity of test compounds was investigated in the hamster isolated trachea (HT) and the endothelium-deprived rabbit isolated pulmonary artery (RPA), two preparations which are endowed with pharmacologically distinct forms of the NK-2 receptor. The novel cyclic pseudopeptides, MEN 10,573 and MEN 10,612 displayed very high affinity for the NK-2 receptor in the HT (pA2 8.66 and 9.06, respectively) which is higher than that observed in the 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 competitive nature in both preparations. MEN 10,573 and MEN 10,612 also displayed competitive antagonism for NK-2 receptor-mediated responses in the rabbit bronchus (RB), rat vas deferens (RVD), circular muscle of the human colon (HUC) and ileum (HUI). In the RB, HUC and HUI, the potency of the novel cyclic pseudopeptides was comparable to that of MDL 29,913 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 that of L659,877. In anaesthetized rats, i.v. injection of MEN 10,612 produced a selective and long-lasting blockade of the urinary bladder contraction produced by the i.v. injection of the NK-2 receptor selective agonist [beta Ala8]neurokinin A(4-10), without affecting the response to the NK-1 receptor selective agonist [Sar9]substance P sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: A. Menarini Pharmaceuticals, Department of Pharmacology, Florence, Italy.
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
authors.forename: L
authors.initials: L
authors.lastname: Quartara
authors.forename: R
authors.initials: R
authors.lastname: Patacchini
authors.forename: S
authors.initials: S
authors.lastname: Giuliani
authors.forename: G
authors.initials: G
authors.lastname: Barbanti
authors.forename: D
authors.initials: D
authors.lastname: Turini
authors.forename: A
authors.initials: A
authors.lastname: Giachetti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*
chemical_list: D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; C084133:MEN 10573; C084134:MEN 10612