Discovery of potent and selective peptide agonists at the GRP-preferring bombesin receptor (BB2)

Analogues of the nonselective bombesin receptor synthetic agonist H‐D‐Phe‐Gln‐Trp‐Ala‐Val‐βAla‐His‐Phe‐Nle‐NH2 were prepared and their biological activity assessed at the NMB‐preferring/bombesin receptor (NMB‐R; BB1), the GRP‐preferring/bombesin receptor (GRP‐R; BB2) and the orphan receptor bombesin receptor subtype‐3 (BRS‐3; BB3). 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 BB1 BB2 and BB3, and for selectivity between these receptor subtypes were established. Synthetic peptides were discovered, which were highly potent agonists at BB2 and extremely selective over both BB1 and BB3. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.