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Submitted on March 24, 2004
Accepted on July 21, 2004
INSERM U469, 141 rue de la Cardonille 34094 Montpellier CEDEX 05 France.; UMR CNRS 7081, 74 route du Rhin BP24, F-67401 Illkirch, France; Sanofi-Synthélabo Recherche, Route d'Espagne, 31100 Toulouse, France and Sanofi-Synthélabo Recherche, Rue du Professeur Blayac, 34000 Montpellier, France
* To whom correspondence should be addressed. E-mail: guillon{at}u469.montp.inserm.fr.
In mammals, the vasopressin V1b receptor (V1b-R) is known to regulate ACTH secretion and more recently stress and anxiety. The characterization of the molecular determinant responsible for its pharmacological selectivity was made possible by the recent discovery of the first V1b antagonist SSR149415. Based upon the structure of the crystallised bovine rhodopsin, we established a three-dimensional molecular model of interaction between the human V1b-R (hV1b-R) and SSR149415. Four amino acids located in distinct transmembrane helices (4th, 5th and 7th) were found potentially responsible for the hV1b-R selectivity. To validate these assumptions, we selectively replaced the Leucine181, Methionine220, Alanine334 and Serine338 residues of hV1a-R by their corresponding amino acids present in the hV1b-R (phenylalanine 164, threonine 203, methionine 324 and asparagine 328 respectively). Four mutants were generated which all exhibited nanomolar affinities for vasopressin and good coupling to phospholipase C (PLC) pathway. hV1a receptors mutated at position 220 and 334 exhibited striking increase in affinity for SS149415 both in binding and PLC assays at variance with the hV1a-R modified at position 181 or 338. In conclusion, this study provides the first structural features concerning the hV1b receptor and highlights the role of few specific residues in its pharmacological selectivity.
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