Eight oxytocin (OT) antagonists with general structure Mpa(1)Sar(7)Arg(8), substituted at position 2 with conformationally constrained and bulky amino acids, were synthesized and pharmacologically tested. Binding affinities and selectivities of compounds for OT, and vasopressin receptor subtypes were investigated. In vitro effects of antagonists were evaluated via inhibition of OT-induced contractions of isolated guinea-pig uterus. The abilities of OT antagonists to inhibit spontaneous contractility in 24 h postpartum rat uterus were investigated. These peptides exhibited pseudoirreversible pharmacological properties, and comprise a novel group of OT antagonists for potential clinical use. Their noncompetitive pharmacological nature can be of therapeutic benefit through a sustained effect on myometrium.

SummaryWe report the solid-phase synthesis and receptor-binding properties of eleven oxytocin analogs (Mpa-XxxIle-Gln-Asn-Cys-Sar-Arg-Gly-NH2) containing non-coded amino acids in position 2: D-a-and L-ot-(2-indanyl)glycine, R,S-6-methoxy-2-aminotetralin-2-carboxylic acid, D-and L-pentafluorophenylalanine, D,L-2,4-dimethylphenylalanine, D,L-2,4,6-trimethylphenylalanine, R,R-and S,S-1,2,3,4-tetrahydro-1-methyl-fl-carboline-3-carboxylic acid and R-and S-1,2,3,4-tetrahydro-fl-carboline-3-carboxylic acid. Some of these amino acid analogs (2-indanylglycine and D-pentafluorophenylalanine) were earlier successfully applied for the synthesis of potent bradykinin antagonists [1,2]. Their receptor bindings were tested on isolated guinea-pig uterus, rat liver and rat kidney inner medulla plasma membranes. The extent of binding of the peptides to the Oxytocin receptor was in several cases was even higher than that of the parent hormone (oxytocin). However, the real pharmacological value of these analogs can be evaluated only after in vivo measurements of their inhibition of uterine motor activity.Abbreviations: Symbols and abbreviations are in accordance with the recommendations of the IUPAC-IUB Joint Commission on Biochemical Nomenclature: Nomenclature and Symbolism for Amino Acids and Peptides [3]. The following other abbreviations were used: AcN,

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