Vasoactive intestinal peptide modification at position 22 allows discrimination between receptor subtypes

Elucidation of the Vasoactive Intestinal Peptide Pharmacophore for VPAC2 Receptors in Human and Rat and Comparison to the Pharmacophore for VPAC1 Receptors

“…One important difference we found from one study (Nicole et al, 2000) was that alanine substitution for Tyr 22 caused a marked decrease in affinity (Ͼ400-fold), whereas it caused only 6.5-fold decrease in the previous study (Nicole et al, 2000). Our results generally agree with a second study (Gourlet et al, 1998), which reported that an Ala 22 substitution in VIP caused a 100-fold decrease in affinity for hVPAC 2 and support the proposal (Gourlet et al, 1998) that an aromatic residue at position 22 of VIP was necessary for high affinity for VPAC 2 . Another difference from a previous study (Nicole et al, 2000) we found was that alanine substitution for Asp 8 or Lys 21 had only a minimal effect on affinity (Ͻ2-to 3-fold decrease), whereas they were reported to cause a Ͼ300-fold and Ͼ60-fold decrease in affinity, respectively (Nicole et al, 2000).…”

“…8,bottom). In a previous study (Gourlet et al, 1998), ]VIP was reported to have a 100-fold higher affinity for VPAC 1 than that for VPAC 2 ; however, we could not confirm this finding.…”

“…7), showing that their side chains were not essential for high affinity VPAC 2 interaction. Our results with alanine scanning show similarities to and differences from the few previous studies that have examined the importance of some amino acids in VIP for high affinity hVPAC 2 interaction (Gourlet et al, 1998;Nicole et al, 2000). One important difference we found from one study (Nicole et al, 2000) was that alanine substitution for Tyr 22 caused a marked decrease in affinity (Ͼ400-fold), whereas it caused only 6.5-fold decrease in the previous study (Nicole et al, 2000).…”

“…8, top) and others (Gourlet et al, 1998;Nicole et al, 2000 , which had a much greater effect on the affinity for hVPAC 2 than for hVPAC 1 , and thus, analogs with these alterations might be useful to develop selective hVPAC 1 agonists. Conversely, alanine substitution for Arg 14 and Val 19 had a greater effect on the affinity for hVPAC 1 than for hVPAC 2 , and this difference could be useful to make selective hVPAC 2 analogs.…”

Antagonistic actions of analogs related to growth hormone-releasing hormone (GHRH) on receptors for GHRH and vasoactive intestinal peptide on rat pituitary and pineal cells in vitro

“…Inhibitory effects of peptide analogs on the VIP-induced PRL release in the rat pituitary cell superfusion system increase VPAC 1 -R antagonistic potency, because their potent and selective VPAC 1 -R antagonist PG 97-269 contains these substitutions (29). Tyr 22 was expected to increase the binding to VPAC 2 receptors and confer enhanced VPAC 2 -R antagonistic activity to the analog, based on the published observations regarding the importance of an aromatic amino acid residue in position 22 for VPAC 2 -R agonists (35). In agreement with this assumption, JV-1-53 had a strong antagonistic effect on VPAC 2 receptors in addition to its potent VPAC 1 -R inhibitory activity.…”