Abstract

The long-term objectives of this proposal include continued efforts to design improved antagonists of the neurohypophysial hormones and to use them as pharmacological probes of the actions of endogenous neurohypophysial hormones.
Specific aims i nclude attempts to modify existing antagonists of the antidiuretic action of vasopressin to attain greater potency, specificity and stability. Systematic substitutions and deletions will be made and the resulting analogs will be tested for activities by multiple bioassays. Oxytocin antagonists will also be modified in the hopes of improving potency and specificity. In addition, antagonists and agonists will be iodinated to provide potentially useful radioactive ligands for receptor studies. Agonists and antagonists will be used as pharmacological tools to characterize the brainstem receptors that mediate vasopressin's actions on cardiovascular reflexes. If better oxytocin antagonists are designed they will be used to explore the possible involvement of endogenous oxytocin in initiation of labor. Antagonists of the antidiuretic response promise to become useful therapeutic agents for treating water retention in a variety of circumstances. Oxytocin antagonists could be useful for treating uterine hypermotility and, possibly, premature labor.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK001940-32
Application #
3224328
Study Section
Endocrinology Study Section (END)
Project Start
1975-09-01
Project End
1991-02-28
Budget Start
1989-09-01
Budget End
1991-02-28
Support Year
32
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027

  Publications

Manning, M; Chan, W Y; Sawyer, W H (1993) Design of cyclic and linear peptide antagonists of vasopressin and oxytocin: current status and future directions. Regul Pept 45:279-83
Manning, M; Sawyer, W H (1993) Design, synthesis and some uses of receptor-specific agonists and antagonists of vasopressin and oxytocin. J Recept Res 13:195-214
Manning, M; Stoev, S; Bankowski, K et al. (1992) Synthesis and some pharmacological properties of potent and selective antagonists of the vasopressor (V1-receptor) response to arginine-vasopressin. J Med Chem 35:382-8
Manning, M; Przybylski, J; Grzonka, Z et al. (1992) Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids. J Med Chem 35:3895-904
Schmidt, A; Audigier, S; Barberis, C et al. (1991) A radioiodinated linear vasopressin antagonist: a ligand with high affinity and specificity for V1a receptors. FEBS Lett 282:77-81
Sawyer, W H; Lammek, B; Misicka, A et al. (1991) Cyclic and linear vasopressin V1 and V1/V2 antagonists containing arginine in the 4-position. Experientia 47:83-6
Kruszynski, M; Manning, M; Wo, N C et al. (1990) Invertebrate neuropeptides resembling vasotocin and some analogues: synthesis and pharmacological properties. Experientia 46:771-3
Manning, M; Stoev, S; Kolodziejczyk, A et al. (1990) Design of potent and selective linear antagonists of vasopressor (V1-receptor) responses to vasopressin. J Med Chem 33:3079-86
Lammek, B; Bankowski, K; Misicka, A et al. (1989) 2-O-alkyltyrosine derivatives of 1-deamino-arginine-vasopressin: highly specific and potent antidiuretic agonists. J Med Chem 32:244-7
Manning, M; Kruszynski, M; Bankowski, K et al. (1989) Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin. J Med Chem 32:382-91

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