Abstract

The general objective of this project is to develop potent competive antagonists of oxytocin (OT) and to begin studies on the pharmacologic potential of these analogs for inhibiting parturition in rats. The antagonists will be designed by making isosteric substitutions that will preserve most of the steric, conformational and electronic similarities to the hormone and/or known best competive antagonists. Analogs will be evaluated by oxytocic, antidiuretic and pressor bioassays in the rat. Binding assays for the antagonists will be performed with receptors in rat uterine membranes to ascertain the contribution of receptor affinity to antagonist potency. Enzymatically resistant antagonists will be devised by substituting OT's natural amino acids with unnatural amino acids (eg, D-amino acids, etc) in order to inhibit peptide bond hydrolysis by degrading enzymes and to prolong the duration of OT action. The survival of the best antagonist in kidney and liver tissues will be studied in in vitro and in vivo and the half-life in the circulation, to evaluate the contribution of antagonist stability to biological potency. The most potent and specific OT antagonist will be tested for inhibition of milk let-down, in vivo uterine contractions and labor. The successful design of very potent antagonists would make possible basic studies on the role of OT in labor and the eventual testing in humans for prevention of premature labor.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD022567-03
Application #
3322275
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1987-09-01
Project End
1990-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Type
School of Medicine & Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611

  Publications

Faden, Maha A; Krakow, Deborah; Ezgu, Fatih et al. (2009) The Erlenmeyer flask bone deformity in the skeletal dysplasias. Am J Med Genet A 149A:1334-45
Hjorten, Rebecca; Hansen, Uwe; Underwood, Robert A et al. (2007) Type XXVII collagen at the transition of cartilage to bone during skeletogenesis. Bone 41:535-42
Flouret, George; Chaloin, Olivier; Borovickova, Lenka et al. (2006) Design of novel bicyclic analogues derived from a potent oxytocin antagonist. J Pept Sci 12:412-9
Flouret, George; Chaloin, Olivier; Borovickova, Lenka et al. (2006) Analogues of oxytocin antagonists bearing a ureido group in the amino acid side chain at position 4 or 5. J Pept Sci 12:347-53
Seemann, Petra; Schwappacher, Raphaela; Kjaer, Klaus W et al. (2005) Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest 115:2373-81
Krakow, Deborah; Sebald, Eiman T; Pogue, Robert et al. (2003) Analysis of clones from a human cartilage cDNA library provides insight into chondrocyte gene expression and identifies novel candidate genes for the osteochondrodysplasias. Mol Genet Metab 79:34-42
Flouret, George; Chaloin, Olivier; Slaninova, Jirina (2003) Analogues of a potent oxytocin antagonist with truncated C-terminus or shorter amino acid side chain of the basic amino acid at position 8. J Pept Sci 9:393-401
Flouret, George; Majewski, Tadeusz; Balaspiri, Lajos et al. (2002) Antagonists of oxytocin featuring replacement with modified beta-mercaptopropionic acids at position 1. J Pept Sci 8:314-26
Fejgin, M D; Pak, S C; Flouret, G et al. (1998) Comparison of the in vivo activity of different oxytocin antagonists in the pregnant baboon. J Soc Gynecol Investig 5:251-4
Delot, E; Brodie, S G; King, L M et al. (1998) Physiological and pathological secretion of cartilage oligomeric matrix protein by cells in culture. J Biol Chem 273:26692-7

Showing the most recent 10 out of 25 publications