Bombesin receptor antagonists [corrected]. 1. Analogues with deleted, inverted or substituted amino acid residues.
Bombesin is a 14-residue peptide hormone which serves a variety of biological functions, including cell growth control in Swiss 3T3 cultured fibroblasts. It has been also involved in an autocrine system regulating the growth of small cell lung carcinoma. A series of bombesin analogues were developed by amino acid deletion, inversion or substitution in the carboxy-terminal region, identified by the target cell receptor. Their properties were examined for: i) competitive binding assays; ii) mitogenic induction and inhibition assays; iii) effects on early cellular events (inositol phosphates production and protein tyrosine phosphorylation). Inversion of the Trp residue, or deletion of the C-terminal tripeptide amide, induced complete loss of receptor affinity and biological effects. Deletion of the His residue, or its derivatization as His (Dnp) in conjunction with Met deletion or modification, gave rise to compounds with reduced receptor affinity and weak antagonistic properties. Other modifications in the C-terminal tripeptide affected the potency but not the biological profile of the parent peptide. These results indicate the basis for the eventual design of improved, specific bombesin receptor antagonists and stimulate further studies on their possible application in the therapy of human small cell lung cancer.
De Castiglione
R
R
Ricerca & Sviluppo Farmitalia Carlo Erba S.r.l., Milano, Italia.
Gozzini
L
L
Mena
R
R
Brugnolotti
M
M
Ciomei
M
M
Molinari
I
I
Comoglio
P M
PM
Gaudino
G
G
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007293:Inosine Triphosphate / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism
D000596:Amino Acids; D007295:Inositol Phosphates; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; D007293:Inosine Triphosphate; D004247:DNA; D001839:Bombesin; D013936:Thymidine