title: Cyclic peptides as selective tachykinin antagonists.
abstract: Twenty homodetic cyclic peptides based on the C-terminal sequence of substance P were prepared (Table I) by a combination of solid-phase techniques and cyclizations using azide coupling procedures. Incorporation of dipeptide mimics based on substituted gamma-lactams were used in some cases to restrict their conformational mobility. Five of these cyclic peptides were shown to have high tachykinin antagonist activity (pA2 > 6) at NK-2 receptors (rat vas deferens). The two most potent of this series, XVII, cyclo(Gln-Trp-Phe-Gly-Leu-Met) (pA2 = 8.1), and I cyclo(Gln-Trp-Phe(R)Gly[ANC-2]Leu-Met) (pA2 = 6.7), were selective for NK-2 receptors compared with the other tachykinin receptors (Table II).
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Harlow, Essex, England.
authors.forename: B J
authors.initials: BJ
authors.lastname: Williams
authors.forename: N R
authors.initials: NR
authors.lastname: Curtis
authors.forename: A T
authors.initials: AT
authors.lastname: McKnight
authors.forename: J J
authors.initials: JJ
authors.lastname: Maguire
authors.forename: S C
authors.initials: SC
authors.lastname: Young
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
authors.forename: R
authors.initials: R
authors.lastname: Baker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives; D015320:Tachykinins / Q000037:antagonists & inhibitors*; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015320:Tachykinins; D013373:Substance P