GI side-effects of a possible therapeutic GRF analogue in monkeys are likely due to VIP receptor agonist activity

Tetsuhide Ito, Hisato Igarashi, Tapas K. Pradhan, Wei Hou, Samuel A. Mantey, John E. Taylor, William A. Murphy, David H. Coy, Robert T. Jensen

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15 Citations (Scopus)

Abstract

Growth hormone (GH) is used or is being evaluated for efficacy in treatment of short stature, aspects of aging, cardiac disorders, Crohn's disease, and short bowel syndrome. Therefore, we synthesized several stable growth hormone-releasing factor (GRF) analogues that could be therapeutically useful. One potent analog, [D-Ala2,Aib8, 18,Ala9, 15, 16, 22, 24-26,Gab27]hGRF(1-27)NH2 (GRF-6), with prolonged infusion caused severe diarrhea in monkeys; however, it had no side-effects in rats. Because GRF has similarity to VIP/PACAP and VIPomas cause diarrhea, this study investigated the ability of this and other GRF analogues to interact with the VIP/PACAP receptors. Rat VPAC1-R (rVPAC1-R), human VPAC1-R (hVPAC1-R), rVPAC2-R and hVPAC2-R stably transfected CHO and PANC 1 cells were made and T47D breast cancer cells containing native human VPAC1-R and AR4-2J cells containing PAC1-R were used. hGRF(1-29)NH2 had low affinity for both rVPAC1-R and rVPAC2-R while VIP had a high affinity for both receptors. GRF-6 had a low affinity for both rVPAC1-R and rVPAC2-R and very low affinity for the rPAC1-R. VIP had a high affinity, whereas hGRF(1-29)NH2 had a low affinity for both hVPAC1-R and hVPAC2-R. In contrast GRF-6, while having a low affinity for hVPAC2-R, had relatively higher affinity for the hVPAC1-R. In guinea pig pancreatic acini, all GRF analogues were full agonists at the VPAC1-R causing enzyme secretion. These results demonstrate that in contrast to native hGRF(1-29)NH2, GRF-6 has a relatively high affinity for the human VPAC1-R but not for the human VPAC2-R, rat VPAC1-R, rat VPAC2-R or rat PAC1-R. These results suggest that the substituted GRF analog, GRF-6, likely causes the diarrheal side-effects in monkeys by interacting with the VPAC1-R. Furthermore, they demonstrate significant species differences can exist for possible therapeutic peptide agonists of the VIP/PACAP/GRF receptor family and that it is essential that receptor affinity assessments be performed in human cells or from a closely related species.

Original languageEnglish
Pages (from-to)1139-1151
Number of pages13
JournalPeptides
Volume22
Issue number7
DOIs
Publication statusPublished - 2001

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience

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