Development of Simplified Vasoactive Intestinal Peptide Analogs with Receptor Selectivity and Stability for

Vasoactive intestinal peptide (VIP) is a widespread neurotrans-mitter whose physiological and pathophysiological actions are mediated by two receptor classes, VIP/pituitary adenylate cy-clase-activating polypeptide (VPAC) 1 and VPAC2. VIP is a 28-amino acid peptide that is rapidly degraded and simplified; metabolically stable analogs are needed. In this study, we use information from studies of the VIP pharmacophore for VPAC1/ VPAC2 to design nine simplified VIP analogs that could have high affinity and selectivity for each VPAC or that retained high affinity for both VPACs and were metabolically stable. From binding studies of their abilities to directly interact with hVPAC1 (T47D cells, hVPAC1-transfected cells) and hVPAC2 (Sup T1-and VPAC2-transfected cells) and to stimulate adenylate cy-clase in each, two analogs [(Ala2,8,9,11,19,22,24,25,27,28)VI