Synthesis and biological activity of tetragastrin analogues modifying the tryptophan residue.

Yabe, Yuichiro; Morita, Akira; Miura, Chieko; Kobayashi, Shinsaku; Baba, Yoshihiko

doi:10.1248/cpb.25.2731

Cited by 12 publications

(5 citation statements)

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“…Methionine at position 15 functions as a spacer and can be replaced with either Leu or Nle without significant effect on the activity (14). Studies focusing on the Trp (15–17) and Asp (18) residues have shown their importance for binding to the CCK 2 receptor and induction of signaling. Modifications of the C‐terminal Phe have resulted in agonists and antagonists (19–23).…”

Section: Analysis Of Gastrin Analogs Amentioning

confidence: 99%

“…Therefore, this sequence was the basis for this study. The analogs synthesized (Table 1) include: (i) a des‐Phe analog; (ii) para ‐substituted analogs, [Leu 15 , p ‐X‐Phe 17 ]G (11–17), where X = F, Cl, Br, I, OH, CH 3 , NH 2 and NO 2 ; (iii) analogs in which Phe 17 was replaced by hydrophobic amino acids of increasing size, Ala, Abu, Val and Leu; (iv) analogs in which Phe 17 was replaced with a nonaromatic structure (Cha) and by other aromatic amino acids, Trp and d ‐Phe; and (v) an analog in which Phe 17 was replaced with the constrained Tic. CCK‐8 has high affinity for the CCK 2 receptor (25).…”

Section: Analysis Of Gastrin Analogs Amentioning

confidence: 99%

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Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK₂receptor

Ahmed

Wibowo

Gembitsky

et al. 2001

The Journal of Peptide Research

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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), [Leu15,Val17]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, Br, 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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Section: Analysis Of Gastrin Analogs Amentioning

confidence: 99%

Section: Analysis Of Gastrin Analogs Amentioning

confidence: 99%

Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK₂receptor

Ahmed

Wibowo

Gembitsky

et al. 2001

The Journal of Peptide Research

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“…The growth-promoting effects of G17-Gly have been shown to be mediated by a putative, non-CCK receptor by several groups, through a mechanism not involving the C-terminal tetrapeptide sequence Trp-Met-Asp-Phe-NH 2 of G17, which is essential for binding and activation of the CCK 2 receptor [3, 7,23–24,26, 37, 39–40]. Nanomolar and micromolar affinity receptors for G17-Gly on primary tissues and on cultured cell lines have been detected [17, 19, 25, 33, 36, 38, 41].…”

Section: Introductionmentioning

confidence: 99%

Bioactivity of analogs of the N-terminal region of gastrin-17

et al. 2009

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Gastrin-17-Gly (G17-Gly) has been shown to bind to non-CCK nanomolar and micromolar affinity sites on DLD-1 and HT-29 human colonic carcinoma cells and to stimulate cellular proliferation. However, in previous studies, we showed that C-terminal truncation of the gastrin-17 (G17) to the G17 analog G17(1–12) and then to G17(1–6)-NH2 did not remove the ability to bind to DLD-1 cells or to activate proliferation. This implies that residues and/or structural motifs required for bioactivity at these receptors rest in the N-terminal region of G17. In this work, radioligand binding studies conducted with further C-terminally truncated analogs revealed that sequences as short as G17(1–4) still bind to a single receptor with micromolar affinity. Additionally, cell proliferation assays showed that G17(1–12) stimulates proliferation of DLD-1 cells, as of HT-29 cells, but the sequences shorter than G17(1–6)-NH2, including nonamidated G17(1–6), were incapable of stimulating proliferation. These observations indicate that the tetrapeptide pGlu-Gly-Pro-Trp is the minimum N-terminal sequence for binding to the probable growth-promoting site on DLD-1 cells. Since analogs shorter than G17(1–6) are able to bind the receptor, these peptides may be of use for developing selective antagonists.

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“…In seeking to enhance human OT receptor affinity, it was decided to investigate the use of L and D-naphthylalanine as a position 2 substituent in four of our previously reported OT antagonists [30,29,54,68]. 2Nal had previously been utilized in structure/activity studies on tetragastrin and somatostatin analogs [80,81]. Subsequently was utilized in the design of superagonist LHRH analogs [82].…”

Section: Introductionmentioning

confidence: 99%

Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban

et al. 2005

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The peptide oxytocin (OT) antagonist atosiban, approved for tocolytic use in Europe (under the tradename Tractocile), represents an important new therapeutic advance for the treatment of premature labor. This paper presents some new peptide OT antagonists which offer promise as superior tocolytics. The solid phase synthesis is reported of four pairs of L and D-2-naphthylalanine (L/D-2Nal) position-2 modified analogs of the following four oxytocin (OT) antagonists: des-9-glycinamide [1-(beta-mercapto-beta,beta-pentamethylene propionic acid), 2-O-methyltyrosine, 4-threonine]ornithine-vasotocin (desGly-NH(2),d(CH(2))(5)[Tyr(Me)(2),Thr(4)]OVT) (A); the Tyr-NH(2) (9) analog of (A), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2) (9)]OVT (B); the Eda(9) analog of (A), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Eda(9)]OVT (C); and the retro COCH(2)Ph(4-0H)(10) modified analog of (C), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-0H)(10)]OVT (D). The eight new analogs of A-D are (1) desGly-NH(2),d(CH(2))(5)[D-2Nal(2),Thr(4)]OVT, (2) desGly-NH(2),d(CH(2))(5)[2-Nal(2),Thr(4)]OVT, (3) d(CH(2))(5)[D-2Nal(2),Thr(4),Tyr-NH(2) (9)]OVT, (4) d(CH(2))(5)[2Nal(2),Thr(4),Tyr-NH(2) (9)]OVT, (5) d(CH(2))(5)[D-2Nal(2),Thr(4),Eda(9)]OVT, (6) d(CH(2))(5)[2Nal(2),Thr(4),Eda(9)]OVT, (7) d(CH(2))(5)[D-2Nal(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-0H)(10)]OVT, (8) d(CH(2))(5)[2Nal(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-OH)(10)]OVT. Peptides 1-8 were evaluated for agonistic and antagonistic activities in in vitro and in vivo rat bioassays, in rat OT receptor (rOTR) binding assays and in human OT receptor (hOTR) and human vasopressin (VP) vasopressor (V(1a)) receptor (hV(1a)R) binding assays. Also reported are the hOTR and hV(1a)R affinity data for atosiban and for B. None of the eight peptides exhibit oxytocic or vasopressor agonism. Peptides 1-8 exhibit weak antidiuretic agonism (activities in the range 0.014-0.21 U/mg). Peptides 1-6 exhibit potent in vitro (no Mg(2+)) OT antagonism (anti-OT pA(2) values range from 7.63 to 8.08). Peptides 7 and 8 are weaker OT antagonists. Peptides 1-6 are all OT antagonists in vivo (estimated in vivo anti-OT pA(2) values in the range 6.94-7.23). Peptides 1-8 exhibit vasopressor antagonism, anti-V(1a) pA(2) values in the range 5.1-7.65. Peptides 1-8 exhibit high affinities for the rOTR (K(i) values = 0.3-7.8 nM). Peptides 1-4 and B exhibit surprisingly very high affinities for the hOTR; their K(i) values are 0.17, 0.29, 0.07, 0.14 and 0.59 nM, respectively. Peptides 1-4 and B exhibit respectively 449, 263, 1091, 546 and 129 times greater affinity for the hOTR than atosiban (K(i) = 76.4 nM). Peptides 1-4 exhibit high affinities for the hV(1a)R (K(i)s = 1.1 nM, 1.3 nM, 0.19 nM and 0.54 nM, all higher than the hV1(a)R affinities exhibited by atosiban (K(i) = 5.1 nM) and by B (K(i) = 5.26 nM). Because of their strikingly higher affinities for the hOTR than atosiban, peptides 1-4 and B exhibit gains in anti hOT/anti hV(1a) receptor selectivity compared with atosiban of 93, 64, 39, 56 and 127, respectively. These OT antagonists are thus promisi...

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Synthesis and biological activity of tetragastrin analogues modifying the tryptophan residue.

Cited by 12 publications

References 0 publications

Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK₂receptor

Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK₂receptor

Bioactivity of analogs of the N-terminal region of gastrin-17

Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban

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Synthesis and biological activity of tetragastrin analogues modifying the tryptophan residue.

Cited by 12 publications

References 0 publications

Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK2receptor

Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK2receptor

Bioactivity of analogs of the N-terminal region of gastrin-17

Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban

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Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK₂receptor

Importance of the C‐terminal phenylalanine of gastrin for binding to the human CCK₂receptor