Development of selective agonists and antagonists for the human vasoactive intestinal polypeptide VPAC(2) receptor.
Ro 25-1553 is a cyclic VIP derivative with a high affinity for the VPAC(2) receptor subtype. Our goal was to identify the modifications that support its selectivity for VPAC(2) receptors, and to develop a VIP or Ro 25-1553 analog behaving as a high affinity, VPAC(2) selective antagonist. The selectivity of Ro 25-1553 for the human receptor was supported mainly by the acetylation of the amino-terminus, by the introduction of a lysine residue in position 12, and by the carboxyl-terminal extension. The lactam bridge created between positions 21 and 25 contributed to the affinity of the compound for the VIP receptors but participated only marginally to its selectivity. Deletion of the first five aminoacid residues led to a low affinity antagonist with a low selectivity. Introduction of a D-Phe residue in position 2 reduced the affinity, the selectivity and the intrinsic activity, the compound being a partial agonist. Myristoylation of the amino-terminus of [K(12)]VIP(1-26) extended carboxyl-terminally with the -K-K-G-G-T sequence of Ro 25-1553 led to a high affinity, selective VPAC(2) receptor antagonist. This molecule represents the first selective human VPAC(2) receptor antagonist described to date.
Moreno
D
D
Department of Biochemistry and Nutrition, Faculty of Medicine, Université Libre de Bruxelles, Bat G/E, CP 611, 808 route de Lennik, B-1070, Brussels, Belgium.
Gourlet
P
P
De Neef
P
P
Cnudde
J
J
Waelbroeck
M
M
Robberecht
P
P
D000215:Acylation; D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D019814:Myristic Acid / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D013379:Substrate Specificity; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D010446:Peptide Fragments; D010456:Peptides, Cyclic; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D011994:Recombinant Proteins; C089777:Ro 25-1553; D014665:Vasodilator Agents; D019814:Myristic Acid; D014660:Vasoactive Intestinal Peptide; D000262:Adenylyl Cyclases