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, Robert T. Jensen

研究成果: ジャーナルへの寄稿記事

29 引用 (Scopus)

抄録

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 T1 cells 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, Thr10, Arg12, Tyr22, and Leu23, whereas the side chains of Ser2, Asp8, Asn9, Gln16, Val19, Lys20, Asn24, and Ser25 are not essential. Comparison of the VIP pharmacophore between hVPAC1 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.

元の言語英語
ページ(範囲)445-460
ページ数16
ジャーナルJournal of Pharmacology and Experimental Therapeutics
303
発行部数2
DOI
出版物ステータス出版済み - 11 1 2002

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Receptors, Vasoactive Intestinal Peptide, Type II
Receptors, Vasoactive Intestinal Polypeptide, Type I
Vasoactive Intestinal Peptide
Amino Acids
Cricetulus
Alanine
Neurotransmitter Agents
Ovary
Pharmacology

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

これを引用

Elucidation of the vasoactive intestinal peptide pharmacophore for VPAC2 receptors in human and rat and comparison to the pharmacophore for VPAC1 receptors. / Igarashi, Hisato; Ito, Tetsuhide; Pradhan, Tapas K.; Mantey, Samuel A.; Hou, Wei; Coy, David H.; Jensen, Robert T.

:: Journal of Pharmacology and Experimental Therapeutics, 巻 303, 番号 2, 01.11.2002, p. 445-460.

研究成果: ジャーナルへの寄稿記事

Igarashi, Hisato ; Ito, Tetsuhide ; Pradhan, Tapas K. ; Mantey, Samuel A. ; Hou, Wei ; Coy, David H. ; Jensen, Robert T. / Elucidation of the vasoactive intestinal peptide pharmacophore for VPAC2 receptors in human and rat and comparison to the pharmacophore for VPAC1 receptors. :: Journal of Pharmacology and Experimental Therapeutics. 2002 ; 巻 303, 番号 2. pp. 445-460.
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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 T1 cells 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, Thr10, Arg12, Tyr22, and Leu23, whereas the side chains of Ser2, Asp8, Asn9, Gln16, Val19, Lys20, Asn24, and Ser25 are not essential. Comparison of the VIP pharmacophore between hVPAC1 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.",
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AU - Igarashi, Hisato

AU - Ito, Tetsuhide

AU - Pradhan, Tapas K.

AU - Mantey, Samuel A.

AU - Hou, Wei

AU - Coy, David H.

AU - Jensen, Robert T.

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