PT - JOURNAL ARTICLE AU - R Patacchini AU - L Quartara AU - M Astolfi AU - C Goso AU - A Giachetti AU - C A Maggi TI - Activity of cyclic pseudopeptide antagonists at peripheral tachykinin receptors. DP - 1995 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1082--1087 VI - 272 IP - 3 4099 - http://jpet.aspetjournals.org/content/272/3/1082.short 4100 - http://jpet.aspetjournals.org/content/272/3/1082.full SO - J Pharmacol Exp Ther1995 Mar 01; 272 AB - The cyclic pseudopeptides MEN 10,548, MEN 10,581, MEN 10,619, MEN 10,677, MEN 10,777 and MEN 10,867 were studied at tachykinin neurokinin (NK)1, NK2 and NK3 receptors on several in vitro bioassays. All compounds were potent and competitive antagonists at tachykinin NK1 and NK2 receptors of the guinea-pig ileum, rabbit pulmonary artery and hamster trachea, showing the highest affinity for the hamster NK2 receptor (e.g., MEN 10,677: pKB = 9.3). By contrast, none showed affinity for NK3 receptors of the rat portal vein, up to 3 microM. In the guinea-pig isolated bronchus, the pseudopeptide compounds competitively antagonized the NK2 receptor-selective agonist [beta Ala8]-NKA (4-10) with potencies comparable to those shown at the rabbit NK2 receptor. In addition, the pseudopeptides were from 3.5-fold (MEN 10,677) to 16-fold (MEN 10548) more potent antagonists against septide than against [Sar9]SP sulfone, two agonists reportedly selective for two distinct sites/subtypes of the NK1 receptor. In binding experiments at human IM9 cells, the pseudopeptide compounds displaced [3H]substance P from human NK1 receptor, showing similar affinities to those displayed at the NK1 receptor in the guinea-pig ileum or bronchus against substance P methylester or septide, as agonists, respectively. This new class of pseudopeptide antagonists, by showing a comparable and high affinity at both tachykinin NK1 and NK2 receptors, might be proposed for treatment/prevention of airway diseases in which endogenous tachykinins play a role by activation of both receptors.