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Discovery of potent and selective peptide agonists at the GRP‐preferring bombesin receptor (BB 2 )
Author(s) -
Darker John G.,
Brough Stephen J.,
Heath Jennie,
Smart Darren
Publication year - 2001
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.359
Subject(s) - bombesin , agonist , chemistry , receptor , peptide , functional selectivity , cricetulus , partial agonist , alanine , stereochemistry , biochemistry , amino acid , neuropeptide , chinese hamster ovary cell
Analogues of the nonselective bombesin receptor synthetic agonist H‐ D ‐Phe‐Gln‐Trp‐Ala‐Val‐βAla‐His‐Phe‐Nle‐NH 2 were prepared and their biological activity assessed at the NMB‐preferring/bombesin receptor (NMB‐R; BB 1 ), the GRP‐preferring/bombesin receptor (GRP‐R; BB 2 ) and the orphan receptor bombesin receptor subtype‐3 (BRS‐3; BB 3 ). Progressive N ‐terminal deletions identified the minimum C ‐terminal sequences required for maintaining a significant agonist effect, whilst an alanine scan, targeted changes in stereochemistry and other pertinent substitutions identified key side‐chain and stereochemical requirements for activation. Key structural elements required for functional potency at BB 1 BB 2 and BB 3 , and for selectivity between these receptor subtypes were established. Synthetic peptides were discovered, which were highly potent agonists at BB 2 and extremely selective over both BB 1 and BB 3 . Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.