title: Antagonists for the neurokinin NK-3 receptor evaluated in selective receptor systems.
abstract: 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 beta-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 [beta-Ala8]-NKA (4-10) and MePhe in position 7 of [beta-Ala8]-NKB (4-10). Antagonism is selective for NKB or [MePhe7]-NKB, and appears to be specific, since the most active compound [Trp7, beta-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.
authors.affiliation: Department of Pharmacology, Medical School, University of Sherbrooke, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Drapeau
authors.forename: N
authors.initials: N
authors.lastname: Rouissi
authors.forename: F
authors.initials: F
authors.lastname: Nantel
authors.forename: N E
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: C
authors.initials: C
authors.lastname: Tousignant
authors.forename: D
authors.initials: D
authors.lastname: Regoli
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D004285:Dogs; D066298:In Vitro Techniques; D015288:Neurokinin A / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*
chemical_list: D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015288:Neurokinin A