Structure-activity relationships of novel vasopressin antagonists containing C-terminal diaminoalkanes and (aminoalkyl)guanidines

We report the synthesis and biological activity of a series of analogues of the vasopressin antagonists [Pmp1,D-Tyr(Et)2,Val4]arginine-vasopressin (1) and [Pmp1,D-Tyr(Et)2,Val4,desGly9]arginine-vasopressin (2), where part or all of the tripeptide tail has been replaced by a simple alkyldiamine [NH(C...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1989-02, Vol.32 (2), p.391-396
Main Authors: Callahan, James F, Ashton-Shue, Daryl, Bryan, Heidemarie G, Bryan, William M, Heckman, Grace D, Kinter, Lewis B, McDonald, Jeanne E, Moore, Michael L, Schmidt, Dulcie B
Format: Article
Language:English
Subjects:
Animals
Chemistry
Exact sciences and technology
Humans
Male
Molecular Conformation
Organic chemistry
Peptides
Peptides - chemical synthesis
Peptides - pharmacology
Preparations and properties
Rats
Receptors, Angiotensin - drug effects
Receptors, Vasopressin
Structure-Activity Relationship
Swine
Vasopressins - antagonists & inhibitors
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Summary:We report the synthesis and biological activity of a series of analogues of the vasopressin antagonists [Pmp1,D-Tyr(Et)2,Val4]arginine-vasopressin (1) and [Pmp1,D-Tyr(Et)2,Val4,desGly9]arginine-vasopressin (2), where part or all of the tripeptide tail has been replaced by a simple alkyldiamine [NH(CH2)nNH2] or (aminoalkyl)guanidine [NH(CH2)nNHC(= NH)NH2] in order to examine the effects that variation of the length and orientation of the tripeptide tail have on renal vasopressin (V2) receptor antagonist activity. The results show that the entire tripeptide tail (Pro-Arg-Gly-NH2) can be replaced by an alkyldiamine or an (aminoalkyl)guanidine, compounds 15 and 16, respectively, indicating that there is no orientational requirement for the basic functional group coming off the cyclic hexapeptide ring. Also, there seems to be an "optimal" distance between the basic functional group and the hexapeptide ring since receptor affinity of the antagonists begins to fall off when the basic functional group is too close (compound 13) or extends too far (compounds 8-10) from the hexapeptide ring. These results suggest all that is necessary for retention of antagonist affinity and potency is a basic functional group, amine or guanidine, extended an optimal distance from the hexapeptide ring.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00122a017