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-betaAla-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.
Darker
J G
JG
Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM 19 5AW, UK. john_darker-1@gsk.com
Brough
S J
SJ
Heath
J
J
Smart
D
D
D000409:Alanine / Q000737:chemistry / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001839:Bombesin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D019886:Gastrin-Releasing Peptide / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007938:Leukemia / Q000473:pathology; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018004:Receptors, Bombesin / Q000819:agonists* / Q000378:metabolism; D018002:Receptors, Bradykinin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D009842:Oligopeptides; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018004:Receptors, Bombesin; D018002:Receptors, Bradykinin; C107120:bombesin receptor subtype 3; D019886:Gastrin-Releasing Peptide; D000409:Alanine; D001839:Bombesin; D002118:Calcium