Partial agonist activity of the bombesin-receptor antagonist [Leu14-ψ-CH2-NH-Leu13]-bombesin in frog peptic cells

doi:10.1016/S0006-291X(88)80994-X

Biochemical and Biophysical Research Communications

Volume 157, Issue 3, 30 December 1988, Pages 1154-1158

https://doi.org/10.1016/S0006-291X(88)80994-X Get rights and content

The pseudopeptide [Leu¹⁴-ψ-CH₂NH-Leu¹³]-bombesin inhibited ¹²⁵I-GRP binding to membrane preparations of frog cerebrum and peptic cells, rat cerebral cortex and pancreas with IC₅₀ ′s of 44–250 nM (using 180 pM ¹²⁵I-GRP). It was unable to stimulate amylase release from rat pancreatic acini, but antagonized competitively BB stimulated amylase release with an IC₅₀ of 130 nM. By contrast the pseudopeptide stimulated pepsinogen secretion from frog esophageal peptic cells with an efficacy relative to bombesin of 36%, and with an EC₅₀ of 30 nM. By virtue of its partial agonist activity it inhibited submaximal BB stimulated responses to a level equal to the pseudopeptide alone. Thus [Leu¹⁴-ψ-CH₂NH-Leu¹³]-BB differentiates certain BB receptors by exhibiting selective intrinsic efficacy.

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The mammalian bombesin (Bn) peptides neuromedin B (NMB) and gastrin-releasing peptide (GRP) actions are mediated by two receptors (NMB-receptor, GRP-receptor) which are widely distributed in the GI tract and CNS. From primarily animal studies NMB/GRP-receptor activation has physiological/pathophysiological effects in the CNS and GI tract including stimulating of growth of cancers and normal tissues. Whereas these Bn-receptors’ effects have been extensively studied in nonhuman cells and animals, little is known of the physiological/pathological role(s) in humans, largely due to lack of potent antagonists. To address this issue we compared NMB/GRP-receptor affinity/potency of 10 chemical classes of putative antagonists (35 compounds) for human Bn-receptors by performing binding studies or assessing abilities to activate hGRP/hNMB-receptor [assessing phospholipase C activation] in four different cells containing native Bn-receptors or transfected receptors. From binding studies 23 were GRP-receptor-preferring, 4 were NMB-receptor, and 8 nonselective. For the hGRP-receptor-preferring analogues none showed hGRP-receptor agonist activity, but 13 were full or partial hNMB-receptor agonists at hNMB-receptors. For hNMB-receptor-preferring analogues none were agonists. Analogue #24 ([(3-Ph-Pr⁶), His⁷, d-Ala¹¹, d-Pro¹³, Ψ(13-14), Phe¹⁴]Bn(6-14)NH₂) and analogue #7 [d-Phe⁶, Leu¹³, Ψ(CH₂NH), Cpa¹⁴]Bn(6-14) were the most potent (0.2–1.4 nM) and selective (>10,000-fold) for the hGRP-receptor with analogue #7.5 [d-Tpi⁶, Leu¹³, Ψ(CH₂NH), Leu¹⁴]Bn(6-14)[RC-3095] (0.2–1.4 nM) slightly less selective. Analogue #34 (PD168368) had the highest affinity for hNMB-receptor (1.32–1.58 nM) and the greatest selectivity (2298–6952-fold) for the hNMB-receptor. These results demonstrate numerous putative hGRP/hNMB-receptor antagonists identified in nonhuman cells and/or animals have agonist activity at the hNMB-receptor, limiting their potential usefulness. However, a number were identified which were potent/selective for human Bn-receptors and should be useful for investigating their roles in human physiological/pathophysiological conditions.
Syntheses and biological activities of bombesin analogs modified in the C-terminal dipeptide part
1997, European Journal of Medicinal Chemistry
Bombesin receptor antagonists are possible therapeutic agents due to their ability to act as inhibitors of cellular proliferation. On the basis of our hypothesis on the mechanism of action of gastrin associating an activating enzyme system to the receptor and on the results reported in the litterature, we have synthesized bombesin analogues which have been modified in the C-terminal Leu¹³-Leu¹⁴ amide part. We have shown that modification in the C-terminal part of the bombesin strongly affected the biological activity in rat pancreatic acini. The most potent compound which is described here, H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Ψ(CH₂)Leu-NH₂, was able to recognize the bombesin receptor on rat pancreatic acini (Ki 4.3 nM) and antagonized the bombesin stimulated amylase secretion (Ki 7.7 nM).
Effects of structural modulation on biological activity of bombesin analogues with (E)-alkene bond
1996, Life Sciences
The specific bombesin receptor antagonist, (E)-alkene bombesin isostere (EABI-1), [D-Phe⁶,Leu¹³Ψ[(E)CHCH]Leu¹⁴]bombesin(6–14) is a potent antagonist in terms of inhibition of bombesin-stimulated amylase release from rat pancreatic acini. This study examined the effects of EABI-1 (L-L diastereomer) and three novel bombesin analogues on amylase release in rat pancreatic acini. EABI-2 is a L-D diastereomer of EABI-1. EABI-3 is an analogue, of which leucine at position 13 of EABI-1 was replaced with valine. EABI-4 is a L-D diastereomer of EABI-3 (L-L). The order of agonist potency was EABI-2 > EABI-3 > EABI-4. EABI-1 showed no agonist activity at concentrations up to 100 nM. On the other hand, all of four analogues had antagonist activity. The order of antagonist potency was EABI-1 > EABI-3 > EABI-4 > EABI-2. EABI-1 was a complete antagonist, EABI-2 and EABI-3 were partial agonists, and EABI-4 had a weak agonist effect. The present study provides a useful information on the future development of peptide analogues for anticancer agents and biological tools for investigating actions of bombesin family peptides.
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1996, Critical Reviews in Oncology/Hematology
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1992, Regulatory Peptides
Several bombesin-receptor antagonists are available that inhibit secretory and growth effects of bombesin, in vitro. In the present study, we examined the effects of a new class of bombesin receptor antagonists (modified GRP(15–27) peptides, with d-Pro²⁶ and d-Ala²⁴ moieties), on bombesin mediated effects, in vivo and in vitro. Of the 10 different compounds tested, BW-10 or 2258U89 ([de-NH₂)Phe¹⁹,d-Ala²⁴,d-Pro²⁶Ψ(CH₂NH)Phe²⁷]-GRP(19–27)) was most potent towards inhibiting bombesin binding to rat pancreatic acinar cancer cells with an ID₅₀ of 0.5 nM. BW-10 (1 and 10 nM) significantly inhibited the gastrin response to 1 nM bombesin, from isolated rat stomach, in vitro, in a dose-dependent fashion. BW-10 (10–100 nmol/kg) was equally effective at significantly inhibiting bombesin evoked gastrin release in anesthetized rats, in vivo. [d-Phe⁶]Bombesin(6–13)-propylamide (BIM), a member of another class of antagonists, reported previously to be the most potent antagonist, in vitro, on the other hand, enhanced bombesin provoked gastrin release in rats. The antagonistic effects of BIM, in vivo, may thus be more selective. Intravenous infusion of BW-10 (10 nmol/kg/h) partially depressed gastrin and pancreatic polypeptide and completely abolished insulin released in response to bombesin, in conscious dogs. These results suggest that BW-10 functions as one of the most potent bombesin receptor antagonists, in vitro and in vivo, which could potentially be used as a therapeutic compound in treatment of some human diseases.
Bombesin-like immunoreactivity in skates and the in vitro effect of bombesin on coronary vessels from the longnose skate, Raja rhina
1991, Regulatory Peptides
Bombesin-like immunoreactivity is present in nerve fibers projecting to the cardiovascular system, including the coronary arteries, and to the gastrointestinal canal, and in endocrine cells of the gut of skates belonging to the family Rajidae.
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Partial agonist activity of the bombesin-receptor antagonist [Leu14-ψ-CH2-NH-Leu13]-bombesin in frog peptic cells

J. Biol. Chem.

Life Sci.

Nature

Nature

Am. J. Physiol.

Partial agonist activity of the bombesin-receptor antagonist [Leu¹⁴-ψ-CH₂-NH-Leu¹³]-bombesin in frog peptic cells