Development of Selective Ligands for Pac1, Vpac1 and Vpac2 Receptors

Abstract

At the time of its isolation, purification and sequencing in 1970-1972 by Said and Mutt (Said and Mutt, 1972;Mutt and Said, 1974), VIP was the third identified member of a peptide group that included secretin (Mutt et al, 1970) and glucagon (Bromer et al, 1957). The family signature was a N-terminal histidylseryl sequence separated by three amino acid residues from a phenylalanylthreonyl sequence. Synthesis of secretin, VIP, glucagon and analogs as well as a careful study of their biological activities revealed that there was no, or only negligible, interference of glucagon with secretin and VIP mediated responses, nor of secretin and VIP with the glucagon response. It was also rapidly recognized that VIP and secretin shared common in vitro properties and that each peptide interacted with its cognate receptor and with the other receptors (Bataille et al, 1974; Robberecht et al, 1976). It was also established for the three peptides that the N-terminal sequence was necessary for the high affinity recognition of the receptor and for induction of the biological activity, and that the C-terminus was necessary for a high affinity recognition. It was thus not possible to shorten significantly the molecule without a loss of the biological properties or peptide potency. This was a major point for the rational design of agonists and antagonists as well as for the interest of industry. Binding studies of125I-labeled peptides characterized the receptors and for each peptide high and low affinity sites were described (Christophe et al, 1976; Laburthe et al, 1978; Prieto et al, 1979).