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Potent V2 vasopressin antagonists with structural changes at their C-terminals
W H Sawyer1, K Bankowski, A Misicka
1Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032.
Peptides
|January 1, 1988
Summary
Structural modifications to antidiuretic (V2) antagonists at their C-terminals maintained potency. These altered peptides show promise as pharmacological tools and potential clinical treatments for water retention.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Endocrinology
Background:
- The antidiuretic hormone arginine-vasopressin (AVP) plays a crucial role in regulating water balance.
- V2 receptor antagonists are essential for managing conditions characterized by excessive water retention.
- Developing potent and specific V2 antagonists requires understanding structure-activity relationships.
Purpose of the Study:
- To investigate the impact of C-terminal structural modifications on the V2-antagonistic activity of AVP derivatives.
- To explore the tolerance of non-peptidic structures at the C-terminus of V2 antagonists.
- To assess the potential of modified antagonists as research tools and therapeutic agents.
Main Methods:
- Synthesis of four parent antidiuretic (V2) antagonists based on d(CH2)5AVP.
- Substitution of the C-terminal 9-glycinamide with various amino acid amides and non-amino acid structures.
- Evaluation of V2-antagonistic potencies in rat models.
Main Results:
- C-terminal modifications, including substitutions with amino acid amides and non-amino acid structures, did not reduce V2-antagonistic potencies.
- The C-terminus of these antagonists can be extended without compromising their potency.
- The parent analogs studied were d(CH2)5[D-Phe2,Ile4]AVP, d(CH2)5[D-Ile2,Ile4]AVP, d(CH2)5[D-Tyr(Et)2, Val4]AVP, and d(CH2)5[D-Tyr(Et)2,Ile4]AVP.
Conclusions:
- C-terminal modifications are well-tolerated in potent V2 antagonists, offering opportunities for structural diversification.
- These modified V2 antagonists hold potential for developing radioactive ligands, affinity labels, and affinity columns for receptor studies.
- The findings support the development of potent, specific V2 antagonists as valuable pharmacological tools and potential clinical treatments for excessive water retention.