Synthesis of oxytocin antagonists containing conformationally constrained amino acids in position 2.
Analogues of oxytocin containing D-Trp, 2-amino-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Atc) or 1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (Car) with R or S configurations in position 2 were synthetized, and their receptor bindings were tested on isolated guinea-pig uterus, rat liver and rat kidney inner medulla plasma membranes. The peptides were synthetized in the solid phase by using racemates of Car and Atc. The resulting diastereomeric mixtures were separated by means of RP-HPLC. The binding to the oxytocin receptor was somewhat decreased for the Atc isomers and dramatically decreased for both R- and S-Car, while the D-Trp-containing analogue displayed a relatively high receptor affinity. However, the V1 receptor affinities were almost the same as those of the parent peptide for the Car-containing analogues and dramatically decreased for the S-Atc substituted analogue, which has a relatively high OT/V1 receptor selectivity of 44.5.
Tóth
G K
GK
Department of Medical Chemistry, Albert Szent-Györgyi Medical University, Szeged, Hungary.
Bakos
K
K
Penke
B
B
Pávó
I
I
Varga
C
C
Török
G
G
Péter
A
A
Fülöp
F
F
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D002243:Carbolines / Q000737:chemistry; D006168:Guinea Pigs; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010121:Oxytocin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D051381:Rats
D065092:Antidiuretic Hormone Receptor Antagonists; D002243:Carbolines; D010455:Peptides; D010121:Oxytocin; C054910:1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid