ACTIVITY OF CYCLIC PSEUDOPEPTIDE ANTAGONISTS AT PERIPHERAL TACHYKININRECEPTORS

The cyclic pseudopeptides MEN 10,548, MEN 10,581, MEN 10,619, MEN 10,6 77, MEN 10,777 and MEN 10,867 were studied at tachykinin neurokinin (N K)(1), NK2 and NK3 receptors on several in vitro bioassays. All compou nds 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: pK(B) = 9.3). By contrast, none showed affinity for N K3 receptors of the rat portal vein, up to 3 mu M. In the guinea-pig i solated bronchus, the pseudopeptide compounds competitively antagonize d the NK2 receptor-selective agonist [beta Ala(8)]-NKA (4-10) with pot encies comparable to those shown at the rabbit NK2 receptor. In additi on, the pseudopeptides were from 3.5-fold (MEN 10,677) to 16-fold (MEN 10548) more potent antagonists against septide than against [Sar(9)]S P sulfone, two agonists reportedly selective for two distinct sites/su btypes of the NK, receptor. In binding experiments at human IM9 cells, the pseudopeptide compounds displaced [H-3]substance P from human NK1 receptor, showing similar affinities to those displayed at the NK1 re ceptor in the guinea-pig ileum or bronchus against substance P methyle ster or septide, as agonists, respectively. This new class of pseudope ptide antagonists, by showing a comparable and high affinity at both t achykinin NK1 and NK2 receptors, might be proposed for treatment/preve ntion of airway diseases in which endogenous tachykinins play a role b y activation of both receptors.