Activity of cyclic pseudopeptide antagonists at peripheral tachykinin receptors.
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.
Patacchini
R
R
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Quartara
L
L
Astolfi
M
M
Goso
C
C
Giachetti
A
A
Maggi
C A
CA
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism*; D011169:Portal Vein / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects
D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3