Synthesis of oxytocin antagonists containing conformationally constrained amino acids in position 2

Analogues of oxytocin containing D-Trp, 2-amino-1,2,3,4-tetrahydronaphthale ne-1-carboxylic acid (Atc) or 1,2,3,4-tetrahydro-beta-carboline-1-carboxyli c acid (Car) with R or S configurations in position 2 were synthetized, and their receptor bindings were tested on isolated guinea-pig uterus, rat liv er and rat kidney inner medulla plasma membranes. The peptides were synthet ized in the solid phase by using racemates of Car and Ate. The resulting di astereomeric mixtures were separated by means of RP-HPLC. The binding to th e oxytocin receptor was somewhat decreased for the Ate isomers and dramatic ally decreased for both R- and S-Car, while the D-Trp-containing analogue d isplayed a relatively high receptor affinity. However, the V-1 receptor aff inities were almost the same as those of the parent peptide for the Car-con taining analogues and dramatically decreased for the S-Atc substituted anal ogue, which has a relatively high OT/V-1 receptor selectivity of 44.5. (C) 1999 Elsevier Science Ltd. All rights reserved.