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Interactions of vasopressin agonists and antagonists with membrane receptors

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Fahrenholz,  Falk
Department of Physical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;

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Boer,  Rainer
Department of Physical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;

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Crause,  Peter
Department of Physical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;

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Fritzsch,  Günter
Department of Physical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Fahrenholz, F., Boer, R., Crause, P., Fritzsch, G., & Grzonka, Z. (1984). Interactions of vasopressin agonists and antagonists with membrane receptors. European Journal of Pharmacology, 100(1), 47-58. doi:10.1016/0014-2999(84)90314-5.


Cite as: http://hdl.handle.net/21.11116/0000-0007-AECA-2
Abstract
Plasma membranes containing one class of non-cooperative binding sites for tritium-labelled [8-arginine]vasopressin were isolated from bovine kidney inner medulla and from rat liver. By using a weighted, non-linear least squares fit to logistic curves, the binding parameters of eight vasopressin agonists and antagonists were determined in competition experiments. Vasopressin analogues with sarcosine or N-methyl-L-alanine in position 7 instead of proline showed a high ratio of antidiuretic to vasopressor activity. These analogues retained a high binding affinity to the renal vasopressin receptor with apparent dissociation constants KD in the order proline less than sarcosine less than methylalanine . In contrast, the affinity to the hepatic vasopressin receptor, which shares characteristics with vasopressor receptors, was drastically reduced with KD values being in the order proline much less than N- methylalanine less than sarcosine. By combining the substitutions at position 7 with substitutions of cysteine in position 1 by either deaminopenicillamine or beta-mercapto-beta, beta-cyclopentamethylenepropionic acid, inhibitors of the oxytocoic and vasopressor responses were obtained. These additional substitutions at position 1 led to a drastic decrease in the binding affinity to the vasopressin receptor in bovine kidney. The intrinsic activity of these analogues to stimulate the renal vasopressin sensitive adenylate cyclase was strongly reduced or completely lost. In the rat liver system, however, these vasopressin antagonists showed a remarkably increased affinity to vasopressin receptors as compared to analogues substituted only at position 7. GTP reduced the binding affinity of all analogues to the hepatic receptor. The results show that these structural modifications which influence both the conformational properties of the vasopressin molecule and the biological activities of the hormone had strikingly different effects on the interactions of the resulting analogues with physiologically important receptors in the kidney and the liver. These studies may lead to the development of more specific vasopressin agonists and antagonists.