A synthetic glycine-extended bombesin analogue interacts with the GRP/bombesin receptor.
alpha-amidation of a peptide (which takes place from a glycine-extended precursor) is required to produce biologically active amidated hormones, such as gastrin-releasing peptide (GRP)/Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH(2) (bombesin). It was shown that glycine-extended gastrin mediates mitogenic effects on various cell lines by interacting with a specific receptor, different from the classical CCK(1) or CCK(2) receptors. On the basis of this observation, we have extended the concept of obtaining active glycine-extended forms of others amidated peptides to produce new active analogues. In this study, we have tested the biological behaviour of a synthetic analogue of the glycine-extended bombesin (para-hydroxy-phenyl-propionyl-Gln-Trp-Ala-Val-Gly-His-Leu-Met-Gly-OH or JMV-1458) on various in vitro models. We showed that compound JMV-1458 was able to inhibit specific (3-[125I]iodotyrosyl(15)) GRP ([125I]GRP) binding in rat pancreatic acini and in Swiss 3T3 cells with K(i) values of approximately 10(-8) M. In isolated rat pancreatic acini, we found that JMV-1458 induced inositol phosphates production and amylase secretion in a dose-dependent manner. In Swiss 3T3 cells, the glycine-extended bombesin analogue dose-dependently produced [3H]thymidine incorporation. By using potent GRP/bombesin receptor antagonists, we showed that this synthetic glycine-extended bombesin analogue induces its biological activities via the classical GRP/bombesin receptor.
Oiry
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Laboratoire des Amino Acides, Peptides et Protéines (L.A.P.P.), UMR CNRS 5810, Universités Montpellier I et II, Faculté de Pharmacie, 15 Av. C. Flahault, 34060 Cedex, Montpellier, France.
Pannequin
J
J
Bernad
N
N
Artis
A M
AM
Galleyrand
J C
JC
Devin
C
C
Cristau
M
M
Fehrentz
J A
JA
Martinez
J
J
D016475:3T3 Cells; D000681:Amylases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007295:Inositol Phosphates / Q000378:metabolism; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018004:Receptors, Bombesin / Q000378:metabolism*
D007295:Inositol Phosphates; D007457:Iodine Radioisotopes; C414675:JMV 1458; D018004:Receptors, Bombesin; D000681:Amylases; D001839:Bombesin