title: Synthesis and in vitro activities of highly potent and selective tripeptide antagonists of the neurokinin NK-1 receptor.
abstract: We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the tripeptide Ac-Thr-D-Trp(CHO)-Phe-N(Me)-Bzl (1, FR113680) partly modified on the C-terminal amide part. Stereochemistry around the benzilic carbon, as well as nitrogen substitution was investigated. Selected compounds were tested on guinea pig ileum for NK-1, rat colon and rat portal vein for NK-2 and NK-3 receptors, respectively. Two of these peptides were shown to have higher tachykinin antagonist activity (pA2 > 8.8) and selectivity for NK-1 receptors compared with compound 1 taken as reference (Table 2). In addition we investigated the stability of compounds 2 and 3 on guinea pig plasma and liver homogenate.
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, Università Federico II, Napoli, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Caliendo
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: P
authors.initials: P
authors.lastname: Grieco
authors.forename: E
authors.initials: E
authors.lastname: Perissutti
authors.forename: V
authors.initials: V
authors.lastname: Santagada
authors.forename: A
authors.initials: A
authors.lastname: Calignano
authors.forename: F
authors.initials: F
authors.lastname: Mancuso
authors.forename: E
authors.initials: E
authors.lastname: Novellino
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C076202:FR 113680