title: [1-deamino-4-cyclohexylalanine] arginine vasopressin: a potent and specific agonist for vasopressin V1b receptors.
abstract: To date, there are no vasopressin (VP) agonists that exhibit a high affinity and selectivity for the VP V1b receptor with respect to the V1a, V2, and oxytocin receptors. In this study, we describe the synthesis and pharmacological properties of [1-deamino-4-cyclohexylalanine] arginine vasopressin (d[Cha4]AVP). Binding experiments performed on various membrane preparations revealed that d[Cha(4)]AVP exhibits a nanomolar affinity for V1b receptors from various mammalian species (rat, bovine, human). It exhibits high V1b/V1a and V1b/oxytocin selectivity for rat, human, and bovine receptors. Furthermore, it exhibits high V1b/V2 specificity for both bovine and human vasopressin receptors. Functional studies performed on biological models that naturally express V1b receptors indicate that d[Cha4]AVP is an agonist. Like VP, it stimulated basal and corticotropin-releasing factor-stimulated ACTH secretion and basal catecholamine release from rat anterior pituitary and bovine chromaffin cells, respectively. In vivo experiments performed in rat revealed that d[Cha4]AVP was able to stimulate both ACTH and corticosterone secretion and exhibits negligible vasopressor activity. It retains about 30% of the antidiuretic activity of VP. This long-sought selective VP V1b receptor ligand with nanomolar affinity will allow a better understanding of V1b-mediated VP physiological effects and is a promising new tool for V1b receptor structure-function studies.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 469, 34094 Montpellier Cedex 05, France.
authors.forename: S
authors.initials: S
authors.lastname: Derick
authors.forename: L L
authors.initials: LL
authors.lastname: Cheng
authors.forename: M J
authors.initials: MJ
authors.lastname: Voirol
authors.forename: S
authors.initials: S
authors.lastname: Stoev
authors.forename: M
authors.initials: M
authors.lastname: Giacomini
authors.forename: N C
authors.initials: NC
authors.lastname: Wo
authors.forename: H H
authors.initials: HH
authors.lastname: Szeto
authors.forename: M
authors.initials: M
authors.lastname: Ben Mimoun
authors.forename: M
authors.initials: M
authors.lastname: Andres
authors.forename: R C
authors.initials: RC
authors.lastname: Gaillard
authors.forename: G
authors.initials: G
authors.lastname: Guillon
authors.forename: M
authors.initials: M
authors.lastname: Manning
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D016466:CHO Cells; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D002838:Chromaffin System / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D006224:Cricetinae; D004231:Diuresis / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D006801:Humans; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018045:Receptors, Oxytocin / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D002395:Catecholamines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; C469699:argipressin, dCha(4)-; D001127:Arginine Vasopressin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone