Synthesis and pharmacological evaluation of an analogue of the peptide hormone oxytocin that contains a mimetic of an inverse gamma-turn.
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.
Yuan
ZhongQing
Z
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Blomberg
David
D
Sethson
Ingmar
I
Brickmann
Kay
K
Ekholm
Kjell
K
Johansson
Birgitta
B
Nilsson
Anders
A
Kihlberg
Jan
J
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
D010456:Peptides, Cyclic; D010121:Oxytocin