Importance of the C-terminal phenylalanine of gastrin for binding to the human CCK2 receptor

S. I. Ahmed, F. Wibowo, D. S. Gembitsky, Z. Bozsó, R. F. Murphy, Sándor Lovas

Research output: Contribution to journalArticle

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Abstract

The importance of the C-terminal Phe of gastrin and structural requirements at position 17 for binding to the human CCK2 receptor were assessed using analogs of [Leu15]G(11-17). The following peptides were synthesized, Ac[Leu15]G(11-17), Ac[Leu15]G(11-16)NH2, [Leu15]G(11-17), [Leu15, Ala17]G(11-17), [Leu15, Abu17]G(11-17), [Leu15Val17] G(11-17), [Leu15, Leu17]G(11-17), [Leu15, Cha17]G(11-17), [Leu15, Trp17]G(11-17), [Leu15, Tic17]G(11-17), [Leu15, D-Phe17] G(11-17) and [Leu15, p-X-Phe17]G(11-17), where X=F, Cl, Bt, I, OH, CH3, NH2 and NO2. Competition binding experiments with [3H]CCK-8 were performed using human CCK2 receptors stably expressed in CHO cells. Phe17 was shown to be important for binding. A hydrophobic side-chain larger than Leu is required at position 17 but aromaticity does not appear to be essential. Constraint of the aromatic side-chain either in the g(+) or g(-) conformation, as in the case of Tic, results in a significant decrease in affinity. In addition, the peptide conformation induced by incorporation of D-Phe decreases binding. The size and electron withdrawing/donating properties of the para substituent are not important for interaction with the receptor. The current study shows that the use of des-Phe analogs of gastrin is not a viable strategy for development of antagonists for the human CCK2 receptor.

Original languageEnglish
Pages (from-to)332-337
Number of pages6
JournalJournal of Peptide Research
Volume58
Issue number4
DOIs
StatePublished - 2001

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Cholecystokinin B Receptor
Gastrins
Phenylalanine
Conformations
Tics
Sincalide
Peptides
CHO Cells
Human Development
Electrons
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology

Cite this

Importance of the C-terminal phenylalanine of gastrin for binding to the human CCK2 receptor. / Ahmed, S. I.; Wibowo, F.; Gembitsky, D. S.; Bozsó, Z.; Murphy, R. F.; Lovas, Sándor.

In: Journal of Peptide Research, Vol. 58, No. 4, 2001, p. 332-337.

Research output: Contribution to journalArticle

Ahmed, S. I. ; Wibowo, F. ; Gembitsky, D. S. ; Bozsó, Z. ; Murphy, R. F. ; Lovas, Sándor. / Importance of the C-terminal phenylalanine of gastrin for binding to the human CCK2 receptor. In: Journal of Peptide Research. 2001 ; Vol. 58, No. 4. pp. 332-337.
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abstract = "The importance of the C-terminal Phe of gastrin and structural requirements at position 17 for binding to the human CCK2 receptor were assessed using analogs of [Leu15]G(11-17). The following peptides were synthesized, Ac[Leu15]G(11-17), Ac[Leu15]G(11-16)NH2, [Leu15]G(11-17), [Leu15, Ala17]G(11-17), [Leu15, Abu17]G(11-17), [Leu15Val17] G(11-17), [Leu15, Leu17]G(11-17), [Leu15, Cha17]G(11-17), [Leu15, Trp17]G(11-17), [Leu15, Tic17]G(11-17), [Leu15, D-Phe17] G(11-17) and [Leu15, p-X-Phe17]G(11-17), where X=F, Cl, Bt, I, OH, CH3, NH2 and NO2. Competition binding experiments with [3H]CCK-8 were performed using human CCK2 receptors stably expressed in CHO cells. Phe17 was shown to be important for binding. A hydrophobic side-chain larger than Leu is required at position 17 but aromaticity does not appear to be essential. Constraint of the aromatic side-chain either in the g(+) or g(-) conformation, as in the case of Tic, results in a significant decrease in affinity. In addition, the peptide conformation induced by incorporation of D-Phe decreases binding. The size and electron withdrawing/donating properties of the para substituent are not important for interaction with the receptor. The current study shows that the use of des-Phe analogs of gastrin is not a viable strategy for development of antagonists for the human CCK2 receptor.",
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AU - Ahmed, S. I.

AU - Wibowo, F.

AU - Gembitsky, D. S.

AU - Bozsó, Z.

AU - Murphy, R. F.

AU - Lovas, Sándor

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N2 - The importance of the C-terminal Phe of gastrin and structural requirements at position 17 for binding to the human CCK2 receptor were assessed using analogs of [Leu15]G(11-17). The following peptides were synthesized, Ac[Leu15]G(11-17), Ac[Leu15]G(11-16)NH2, [Leu15]G(11-17), [Leu15, Ala17]G(11-17), [Leu15, Abu17]G(11-17), [Leu15Val17] G(11-17), [Leu15, Leu17]G(11-17), [Leu15, Cha17]G(11-17), [Leu15, Trp17]G(11-17), [Leu15, Tic17]G(11-17), [Leu15, D-Phe17] G(11-17) and [Leu15, p-X-Phe17]G(11-17), where X=F, Cl, Bt, I, OH, CH3, NH2 and NO2. Competition binding experiments with [3H]CCK-8 were performed using human CCK2 receptors stably expressed in CHO cells. Phe17 was shown to be important for binding. A hydrophobic side-chain larger than Leu is required at position 17 but aromaticity does not appear to be essential. Constraint of the aromatic side-chain either in the g(+) or g(-) conformation, as in the case of Tic, results in a significant decrease in affinity. In addition, the peptide conformation induced by incorporation of D-Phe decreases binding. The size and electron withdrawing/donating properties of the para substituent are not important for interaction with the receptor. The current study shows that the use of des-Phe analogs of gastrin is not a viable strategy for development of antagonists for the human CCK2 receptor.

AB - The importance of the C-terminal Phe of gastrin and structural requirements at position 17 for binding to the human CCK2 receptor were assessed using analogs of [Leu15]G(11-17). The following peptides were synthesized, Ac[Leu15]G(11-17), Ac[Leu15]G(11-16)NH2, [Leu15]G(11-17), [Leu15, Ala17]G(11-17), [Leu15, Abu17]G(11-17), [Leu15Val17] G(11-17), [Leu15, Leu17]G(11-17), [Leu15, Cha17]G(11-17), [Leu15, Trp17]G(11-17), [Leu15, Tic17]G(11-17), [Leu15, D-Phe17] G(11-17) and [Leu15, p-X-Phe17]G(11-17), where X=F, Cl, Bt, I, OH, CH3, NH2 and NO2. Competition binding experiments with [3H]CCK-8 were performed using human CCK2 receptors stably expressed in CHO cells. Phe17 was shown to be important for binding. A hydrophobic side-chain larger than Leu is required at position 17 but aromaticity does not appear to be essential. Constraint of the aromatic side-chain either in the g(+) or g(-) conformation, as in the case of Tic, results in a significant decrease in affinity. In addition, the peptide conformation induced by incorporation of D-Phe decreases binding. The size and electron withdrawing/donating properties of the para substituent are not important for interaction with the receptor. The current study shows that the use of des-Phe analogs of gastrin is not a viable strategy for development of antagonists for the human CCK2 receptor.

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