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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Hisato Igarashi, Tetsuhide Ito, Tapas K. Pradhan, Samuel A. Mantey, Wei Hou, David H. Coy and Robert T. Jensen
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 445-460; DOI: https://doi.org/10.1124/jpet.102.038075
Hisato Igarashi
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Tetsuhide Ito
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Tapas K. Pradhan
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Samuel A. Mantey
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Wei Hou
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David H. Coy
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Robert T. Jensen
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Abstract

Vasoactive intestinal peptide (VIP) functions as a neurotransmitter involved in a number of physiological and pathological conditions. The actions of VIP are mediated through VPAC1 and VPAC2. In contrast to VPAC1, which has been extensively studied, little is known about the pharmacology of VPAC2. In this study we investigated the VIP pharmacophore for VPAC2 by using alanine and d-amino acid scanning. We found significant species differences, and the human VPAC2 (hVPAC2) expressed in Chinese hamster ovary (CHO) cells, which have been used in previous studies, differed significantly from the native hVPAC2 in Sup T1cells and hVPAC2 expressed in PANC1 cells. There was a close agreement between binding affinities and potencies for VPAC2 activation. The amino acids whose backbone or side chain orientations were most important for high affinity potency are Asp3, Phe6, Thr7, Tyr10, Arg12, Tyr22, and Leu23, whereas the side chains of Ser2, Asp8, Asn9, Gln16, Val19, Lys20, Lys21, Asn24, and Ser25 are not essential. Comparison of the VIP pharmacophore between hVPAC1 and hVPAC2 demonstrated that the side chains of Thr7, Tyr10, Thr11, and Tyr22 were much more critical for high affinity for the hVPAC2 than the hVPAC1. In contrast, the orientation of the side chain of Asn24 was more important for high affinity for the hVPAC1. This study shows that in assessing the pharmacophore of VIP analogs for the VPAC2, important species differences need to be considered as well as the expression system used. These results of our study should be useful for designing VPAC subtype-selective analogs, simplified analogs, and possibly metabolically stable analogs.

Footnotes

  • DOI: 10.1124/jpet.102.038075

  • Abbreviations:
    VIP
    vasoactive intestinal peptide
    VPAC
    for official nomenclature, see Harmer et al., 1998
    VPAC1
    VPAC1-receptor
    VPAC2
    VPAC2-receptor
    hVPAC
    human VPAC receptor
    rVPAC
    rat VPAC receptor
    CHO
    Chinese hamster ovary
    hVPAC2/CHO
    hVPAC2 stably transfected CHO cells
    rVPAC2/CHO rVPAC2 stably transfected CHO cells
    hVPAC2/PANC1, hVPAC2 stably transfected PANC1 cells
    rVPAC2/PANC1
    rVPAC2 stably transfected PANC1 cells
    PANC1
    human pancreatic cancer cell line
    PACAP
    pituitary adenylate cyclase-activating peptide
    G418
    geneticin
    IBMX
    3-isobutyl-1-methylxanthine
    BSA
    bovine serum albumin
    DMEM
    Dulbecco's modified Eagle's medium
    Ro 25-1553
    Ac-His-Ser-Asp-Ala-Val-Phe-Thr-Glu-Asn-Tyr-Thr-Lys-Leu-Arg-Lys-Gln-Nle-Ala-Ala-Lys-cyclo[Lys-Tyr-Leu-Asn-Asp]-Leu-Lys-Lys-Gly-Gly-Thr-NH2
    • Received May 1, 2002.
    • Accepted July 2, 2002.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Hisato Igarashi, Tetsuhide Ito, Tapas K. Pradhan, Samuel A. Mantey, Wei Hou, David H. Coy and Robert T. Jensen
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 445-460; DOI: https://doi.org/10.1124/jpet.102.038075

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Hisato Igarashi, Tetsuhide Ito, Tapas K. Pradhan, Samuel A. Mantey, Wei Hou, David H. Coy and Robert T. Jensen
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 445-460; DOI: https://doi.org/10.1124/jpet.102.038075
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