Synthesis and Pharmacological Evaluation of an Analogue of the Peptide Hormone Oxytocin That Contains a Mimetic of an Inverse γ-Turn

• Published in: Journal of medicinal chemistry 2002-06, Vol.45 (12), p.2512-2519
• Main Authors: Yuan, ZhongQing, Blomberg, David, Sethson, Ingmar, Brickmann, Kay, Ekholm, Kjell, Johansson, Birgitta, Nilsson, Anders, Kihlberg, Jan
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Female; Hormones. Endocrine system; In Vitro Techniques; Isometric Contraction; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Mimicry; Oxytocin - analogs & derivatives; Oxytocin - chemical synthesis; Oxytocin - chemistry; Oxytocin - pharmacology; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Pharmacology. Drug treatments; Protein Structure, Secondary; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Uterus - drug effects; Uterus - physiology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0110744

Oxytocin is a neurohypophyseal peptide hormone that induces labor and lactation in mammals. An inverse γ-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 γ-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 ψ[CH2O] isostere while a covalent methylene bridge replaces the hydrogen bond that is often found between residues i and i + 2 in γ-turns. The turn mimetic was assembled from three types of building blocks:  an azido epoxide, an α-bromo acid, and a protected β-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 ψ[CH2O] isostere instead of an amide bond between residues i and i + 1 in the turn mimetic.