Development of selective agonists and antagonists for the human vasoactive intestinal polypeptide VPAC2 receptor

Ro 25-1553 is identified as the first selective human VPAC(2) receptor antagonist.

• Selectivity for VPAC(2) receptors is primarily supported by modifications such as acetylation of the amino-terminus, introduction of a lysine residue at position 12, and a carboxyl-terminal extension.
• The lactam bridge between positions 21 and 25 contributes to affinity for VIP receptors but only marginally affects selectivity.
• Deletion of the first five amino acids resulted in a low affinity antagonist with low selectivity.
• Addition of a D-Phe residue at position 2 decreased affinity, selectivity, and intrinsic activity, resulting in a partial agonist.
• Myristoylation of the amino-terminus of a specific VIP analog produced a high affinity, selective VPAC(2) receptor antagonist.

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