title: Activity of peptide and non-peptide antagonists at peripheral NK1 receptors.
abstract: We investigated the affinity of several tachykinin antagonists reportedly selective for NK1 receptors at various tachykinin receptors and NK2 receptors subtypes. The four antagonists tested were: L 668,169, Spantide II, Ac-Thr-DTrp(for)-Phe-NMeBzl (FR 113680) and the novel nonpeptide antagonist (+/-)-CP-96,345. The four antagonists were found to be effective against NK1 receptor-mediated responses in the guinea-pig ileum with the following rank order of potency (pKB values in parentheses): (+/-)-CP-96,345 (8.11) greater than Spantide II (7.08) greater than FR 113680 (6.61) greater than or equal to L 558,169 (6.44). (+/-)-CP-96,345, Spantide II and FR 113680 were distinctly more potent at NK1 receptors than at NK2 receptors (NK2A in the rabbit pulmonary artery, NK2B in the hamster trachea). L 668,169 antagonized neurokinin A-induced contractions in the hamster trachea with an affinity similar (pKB value 6.16) to that found in the guinea-pig ileum for NK1 receptors (pKB value 6.44). All antagonists were inactive at NK3 receptors of the rat portal vein. In a second series of experiments, the affinities of test antagonists for NK1 receptors in the guinea-pig ileum were compared to those for NK1 receptors in the guinea-pig vas deferens, the rabbit jugular vein and the rat urinary bladder. For each antagonist, the affinity measured in the guinea-pig vas deferens and the rabbit jugular vein was comparable to that found in the guinea-pig ileum. In the rat urinary bladder, (+/-)-CP-96,345 was about 100 times less potent in blocking NK1 receptor-mediated contractions than in the guinea-pig ileum.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Patacchini
authors.forename: P
authors.initials: P
authors.lastname: Santicioli
authors.forename: M
authors.initials: M
authors.lastname: Astolfi
authors.forename: P
authors.initials: P
authors.lastname: Rovero
authors.forename: G
authors.initials: G
authors.lastname: Viti
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D006224:Cricetinae; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects / Q000648:ultrastructure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000648:ultrastructure; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D018039:Receptors, Tachykinin; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; C076202:FR 113680; C065446:spantide II; C076509:L 668169; D013373:Substance P; C066892:CP 96345