Hexanoylation of a VPAC2 receptor-preferring ligand markedly increased its selectivity and potency.
We synthesized a VIP analog that combines mutations that decrease the affinity for the VPAC1 receptor but maintain a high affinity for the VPAC2 receptor with an amino-terminal hexanoylation that increases the affinity for the VPAC2 receptor with a limited decrease in the affinity of the VPAC1 receptor. The resulting Hexanoyl[A19,K(27,28)]VIP had the expected properties of a high affinity for the VPAC2 receptor and a low affinity for the VPAC1 receptor and also a low affinity for the PAC1 and secretin receptors. With a 1000-fold preference for the VPAC2 receptor and a IC50 value of binding of 1 nM, this compound is the most potent and the most selective agonist presently described.
Langer
Ingrid
I
Department of Biochemistry and Nutrition, School of Medicine, Université Libre de Bruxelles, Bât G/E, CP 611, 808 Route de Lennik, B-1070 Bruxelles, Belgium.
Gregoire
Françoise
F
Nachtergael
Ingrid
I
De Neef
Philippe
P
Vertongen
Pascale
P
Robberecht
Patrick
P
D000818:Animals; D001665:Binding Sites; D006801:Humans; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014660:Vasoactive Intestinal Peptide / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry*
D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C029937:secretin receptor; D014660:Vasoactive Intestinal Peptide