Conformationally restricted analogs of oxytocin; stabilization of inhibitory conformation.
Analogs of oxytocin containing tetrahydroisoquinoline carboxylic acid (Tic) of L or D configuration in position 2 were synthesized and their biological activities were tested. Both analogs showed negligible agonist activity in uterotonic, galactogogic, and pressor assays, but they are in vitro uterotonic inhibitors. In comparison with oxytocin analogs containing L- or D-phenylalanine in position 2, the analog with the D-configuration of the conformationally fixed aromatic residue has significantly increased inhibitory activity which suggests that the proper conformation for the interaction with the receptor, but not for its activation, was stabilized. 1H NMR and CD studies, supported by theoretical calculations, suggest that the conformational properties of the analog containing D-tetrahydroisoquinoline carboxylic acid are similar to those of [2-D-phenylalanine]oxytocin.
Lebl
M
M
Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague.
Hill
P
P
Kazmierski
W
W
Kárászová
L
L
Slaninová
J
J
Fric
I
I
Hruby
V J
VJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002942:Circular Dichroism; D005260:Female; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects
D007202:Indicators and Reagents; D010121:Oxytocin