title: Development of high affinity selective VIP1 receptor agonists.
abstract: The biological effects of VIP are mediated by at least two VIP receptors: the VIP1 and the VIP2 receptors that were cloned in rat, human and mice. As the mRNA coding for each receptor are located in different tissues, it is likely that each receptor modulates different functions. It is therefore of interest to obtain selective agonists for each receptor subtype. In the present work, we achieved the synthesis of two VIP1 receptor selective agonsits derived from secretin and GRF. [R16]chicken secretin had IC50 values of binding of 1,10,000, 20, and 3000 nM for the rat VIP1-, VIP2-, secretion- and PACAP receptors, respectively. This peptide, however, had a weaker affinity for the human VIP1 receptor (IC50 of 60 nM). The chimeric, substituted peptide [K15, R16, L27]VIP(1-7)/GRF(8-27) had IC50 values of binding of 1,10,000, 10,000 and 30,000 nM for the rat VIP1-, VIP2-, secretin- and PACAP receptors, respectively. Furthermore, its also showed an IC50 of 0.8 nM for the human VIP1 receptor and a low affinity for the human VIP2 receptor. It is unlikely that this GRF analogue interacted with a high affinity to the pituitary GRF receptors as it did not stimulate rat pituitary adenylate cyclase activity. The two described analogues stimulated maximally the adenylate cyclase activity on membranes expressing each receptor subtype.
authors.affiliation: Department of Biochemistry and Nutrition, Medical School, Université Libre de Bruxelles, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Gourlet
authors.forename: A
authors.initials: A
authors.lastname: Vandermeers
authors.forename: P
authors.initials: P
authors.lastname: Vertongen
authors.forename: J
authors.initials: J
authors.lastname: Rathe
authors.forename: P
authors.initials: P
authors.lastname: De Neef
authors.forename: J
authors.initials: J
authors.lastname: Cnudde
authors.forename: M
authors.initials: M
authors.lastname: Waelbroeck
authors.forename: P
authors.initials: P
authors.lastname: Robberecht
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists* / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012633:Secretin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D011994:Recombinant Proteins; D012633:Secretin; D014660:Vasoactive Intestinal Peptide; D013007:Growth Hormone-Releasing Hormone; D000262:Adenylyl Cyclases