VASOACTIVE-INTESTINAL-PEPTIDE MODIFICATION AT POSITION-22 ALLOWS DISCRIMINATION BETWEEN RECEPTOR SUBTYPES

Secretin and growth hormone releasing factor (GRF) have a weak affinit y for VIP (vasoactive intestinal peptide)/PACAP (pituitary adenylate c yclase activating polypeptide) receptors, but discriminate between VIP ,/PACAP and VIP,/PACAP receptors. This previously allowed us to develo p modified secretin and GRF derivatives as high affinity and highly se lective VIP,/PACAP receptor ligands. We tested the hypothesis that the presence of a Gla residue at position 24 and a Leu residue at positio n 22 was responsible for their VIP1/PACAP receptor selectivity. [Gln(2 4)]VIP was not different from VIP but [Leu(22)]VIP had a 100-fold lowe r affinity for VIP2/PACAP receptors as compared to VIP1/PACAP receptor s. The substitution of Tyr(22) by Phe(22) in VIP had no significant ef fect on the recognition of both receptors but [Ala(22)]VIP had a reduc ed affinity for the VIP2/PACAP receptor. This indicated that an aromat ic residue at position 22 of VIP was required for a high affinity for the VIP2/PACAP receptor but not for the VIP1/PACAP receptor. (C) 1998 Elsevier Science B.V.