Creation of a Selective Antagonist and Agonist of the Rat VPAC1Receptor Using a Combinatorial Approach with Vasoactive Intestinal Peptide 6–23 as Template

A substitution of alanine with diphenylalanine at position 18 in vasoactive intestinal peptide increased binding efficiency by 370-fold.

• The modified peptide [Tyr(9),Dip(18)]VIP(6-23) exhibits a binding affinity (K(i)) of 90 nM and selectively inhibits VIP-induced cAMP stimulation.
• This analog is a selective antagonist for the VPAC(1) receptor with K(i) values of 3,000 nM and >10,000 nM for the VPAC(2) and PAC(1) receptors, respectively.
• The extended form, [Tyr(9),Dip(18)]VIP(6-28), shows improved antagonistic properties with K(i) and K(b) values of 18 nM and 16 nM.
• In contrast, the fully extended form, [Tyr(9),Dip(18)]VIP(1-28), acts as a potent agonist with a K(i) of 0.11 nM and an EC(50) of 0.23 nM for cAMP stimulation.
• This agonist demonstrates high specificity for the VPAC(1) receptor, with K(i) values of 53 nM for VPAC(2) and 3,100 nM for PAC(1).

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