title: Synthesis and pharmacological evaluation of an analogue of the peptide hormone oxytocin that contains a mimetic of an inverse gamma-turn.
abstract: Oxytocin is a neurohypophyseal peptide hormone that induces labor and lactation in mammals. An inverse gamma-turn mimetic corresponding to the tripeptide Ile-Val-Asn has been synthesized and incorporated instead of residues 3-5 of oxytocin to probe the hypothesis that a gamma-turn involving these residues is found in the receptor bound conformation of oxytocin. In the turn mimetic, residues i and i + 1 are connected by a psi[CH(2)O] isostere while a covalent methylene bridge replaces the hydrogen bond that is often found between residues i and i + 2 in gamma-turns. The turn mimetic was assembled from three types of building blocks: an azido epoxide, an alpha-bromo acid, and a protected beta-amino alcohol. The oxytocin analogue did not induce contractions of the uterus nor did it inhibit oxytocin-induced contractions. It is suggested that the loss of bioactivity is mainly due to the presence of a psi[CH(2)O] isostere instead of an amide bond between residues i and i + 1 in the turn mimetic.
authors.affiliation: Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: ZhongQing
authors.initials: Z
authors.lastname: Yuan
authors.forename: David
authors.initials: D
authors.lastname: Blomberg
authors.forename: Ingmar
authors.initials: I
authors.lastname: Sethson
authors.forename: Kay
authors.initials: K
authors.lastname: Brickmann
authors.forename: Kjell
authors.initials: K
authors.lastname: Ekholm
authors.forename: Birgitta
authors.initials: B
authors.lastname: Johansson
authors.forename: Anders
authors.initials: A
authors.lastname: Nilsson
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
mesh_terms: D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D007537:Isometric Contraction; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000502:physiology
chemical_list: D010456:Peptides, Cyclic; D010121:Oxytocin