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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Development of Simplified Vasoactive Intestinal Peptide Analogs with Receptor Selectivity and Stability for Human Vasoactive Intestinal Peptide/Pituitary Adenylate Cyclase-Activating Polypeptide Receptors

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (H.I., T.I., S.A.M., T.K.P., W.H., D.H.C., R.T.J.); and Peptide Research Laboratories, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana (D.H.C.)

Vasoactive intestinal peptide (VIP) is a widespread neurotransmitter whose physiological and pathophysiological actions are mediated by two receptor classes, VIP/pituitary adenylate cyclase-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 cyclase in each, two analogs [(Ala^{2,8,9,11,19,22,24,25,27,28})VIP and (Ala^{2,8,9,11,19,24–28})VIP] were found to have >2000- and >600-fold selectivity for hVPAC₁. None of the nine analogs had hVPAC₂ selectivity. However, two simplified analogs [(Ala^{2,8,9, 16,19,24})VIP and (Ala^{2,8,9,16,19,24,25})VIP] retained high affinity and potency for both hVPACs. ¹²⁵I-[Ala^{2,8,9,16,19,24,25}]VIP was much more metabolically stable than ¹²⁵I-VIP. The availability of these simplified analogs of VIP, which are metabolically stable and have either hVPAC₁ selectivity or retain high affinity for both hVPACs, should be useful for exploring the role of VPAC subtypes in mediating VIPs' actions as well as being useful therapeutically and for exploring the usefulness of VIP receptor imaging of tumors and VIP receptor-mediated tumor cytotoxicity.

Address correspondence to: Dr. Robert T. Jensen, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 10, Rm. 9C-103, 10 Center Dr. MSC 1804, Bethesda MD 20892-1804. E-mail: robertj{at}bdg10.niddk.nih.gov