Potent bombesin receptor antagonists distinguish receptor subtypes.
To determine whether newly described bombesin (BN) receptor antagonists distinguish subtypes of BN receptors, we investigated their abilities to interact with BN receptors on esophageal muscle or pancreatic acinar tissue. For inhibition of binding of 125I-[Tyr4]BN to rat pancreatic tissue, the relative potencies were [D-Phe6]BN-(6-13)ethyl ester (5 nM) greater than Ac-gastrin-releasing peptide (GRP)-(20-26)ethyl ester (17 nM) greater than [D-Phe6,Cpa,14, psi 13-14]BN-(6-14) (40 nM) greater than [Leu14, psi 13-14]BN (0.43 microM) greater than [Tyr4,D-Phe12]BN = [D-Pro4, D-Trp7,9,10]substance P (SP)-4-11 (13 microM) greater than [Leu14, psi 9,10]BN (32 microM) greater than [D-Arg1,D-Trp7,9,Leu11]SP (70 microM). Each antagonist also inhibited binding of 125I-[Tyr4]BN or 125I-Bolton-Hunter-neuromedin B to rat esophageal tissue, and the potency of each antagonist for each tracer was similar. In comparison to rat pancreas, [D-Phe6]BN-(6-13)ethyl ester, Ac-GRP-(20-26)ethyl ester, [D-Phe6,Cpa14, psi 13-14]BN-(6-14), [Leu14, psi 13-14]BN, and [Leu14, psi 9,10]BN had a 10,000-, 2,940-, 1,425-, 122-, and 4-fold, respectively, weaker affinity for BN receptors. In contrast [Tyr4,D-Phe12]BN, [D-Pro4,D-Trp7,9,10]SP-4-11, and [D-Arg1,D-Trp7,9,Leu11]SP had a 4-, 4-, and 9-fold, respectively, higher affinity compared with pancreatic tissue. Comparison of the activity of each peptide at inhibiting the ability of equipotent concentrations of BN or neuromedin B to stimulate contraction of rat esophageal muscle demonstrated that each peptide had the same relative potencies as for inhibiting binding.(ABSTRACT TRUNCATED AT 250 WORDS)
von Schrenck
T
T
Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Wang
L H
LH
Coy
D H
DH
Villanueva
M L
ML
Mantey
S
S
Jensen
R T
RT
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010179:Pancreas / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis; D051381:Rats; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D010455:Peptides; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; D001839:Bombesin