ANTAGONISTS FOR THE NEUROKININ NK-3 RECEPTOR EVALUATED IN SELECTIVE RECEPTOR SYSTEMS

Four isolated vessels that are monoreceptor systems for neurokinins, the dog carotid artery and rabbit jugular vein (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3), were used to compare the activities of selective neurokinin agonists and evaluate the affinities of new NK-3 antagonists. Chemical modifications in the partial sequences NKA (4-10) and NKB (4-10), particularly the replacement of Val7 with an aromatic residue (Tyr, MePhe or Trp) and the extension of the peptide backbone in position 8, obtained with β-Ala, led to compounds that maintain weak agonistic activities on the NK-1 and NK-2, and some of them also on NK-3 receptors but exert potent antagonism against NKB on the NK-3 receptor of the rat portal vein. Antagonistic affinity is the highest when Trp is used in position 7 of [β-Ala8]-NKA (4-10) and MePhe in position 7 of [β-Ala8]-NKB (4-10). Antagonism is selective for NKB or [MePhe7]-NKB, and appears to be specific, since the most active compound [Trp7,β-Ala8]-NKA (4-10) is inactive against bradykinin on the rabbit jugular vein (B2 receptor), against SP on the rabbit jugular vein (NK-1 receptor), against desArg9-bradykinin on the rabbit aorta (B1 receptor), and against angiotensin II and histamine (AT and H receptors, respectively) in the rabbit aorta. The new NK-3 receptor antagonists described in the present study provide useful tools for neurokinin receptor characterization and for determining the roles of neurokinins in physiopathology. © 1990.