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J. Biol. Chem., Vol. 276, Issue 12, 9219-9229, March 23, 2001
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From the The orphan receptor, bombesin (Bn)
receptor subtype 3 (BRS-3), shares high homology with bombesin
receptors (neuromedin B receptor (NMB-R) and gastrin-releasing peptide
receptor (GRP-R)). This receptor is widely distributed in the central
nervous system and gastrointestinal tract; target disruption leads to
obesity, diabetes, and hypertension, however, its role in physiological and pathological processes remain unknown due to lack of selective ligands or identification of its natural ligand. We have recently discovered (Mantey, S. A., Weber, H. C., Sainz, E., Akeson,
M., Ryan, R. R. Pradhan, T. K., Searles, R. P., Spindel,
E. R., Battey, J. F., Coy, D. H., and Jensen, R. T. (1997) J. Biol. Chem. 272, 26062-26071) that
[D-Tyr6,
Rational Design of a Peptide Agonist That Interacts Selectively
with the Orphan Receptor, Bombesin Receptor Subtype 3*
,,,,,,¶
Digestive Diseases Branch, NIDDK, National
Institutes of Health, Bethesda, Maryland 20892 and the
§ Department of Medicine, Peptide Research, Tulane
University Health Sciences Center, New Orleans, Louisiana 70112
-Ala11,Phe13,Nle14]Bn-(6-14)
has high affinity for BRS-3 and using this ligand showed BRS-3 has a
unique pharmacology with high affinity for no known natural Bn
peptides. However, use of this ligand is limited because it has high
affinity for all known Bn receptors. In the present study we have
attempted to identify BRS-3 selective ligands using a strategy of
rational peptide design with the substitution of conformationally
restricted amino acids into the prototype ligand [D-Tyr6,-Ala11,Phe13,Nle14]Bn-(6-14)
or its D-Phe6 analogue. Each of the 22 peptides
synthesized had binding affinities determined for hBRS-3, hGRPR, and
hNMBR, and hBRS-3 selective ligands were tested for their ability to
activate phospholipase C and increase inositol phosphates
([3H]inositol phosphate). Using this approach we
have identified a number of BRS-3 selective ligands. These ligands
functioned as receptor agonists and their binding affinities were
reflected in their potencies for altering [3H]inositol
phosphate. Two peptides with an (R)- or
(S)-amino-3-phenylpropionic acid substitution for
-Ala11 in the prototype ligand had the highest
selectivity for the hBRS-3 over the mammalian Bn receptors and did not
interact with receptors for other gastrointestinal
hormones/neurotransmitters. Molecular modeling demonstrated these two
selective BRS-3 ligands had a unique conformation of the position 11 -amino acid. This selectivity was of sufficient magnitude that these
should be useful in explaining the role of hBRS-3 activation in
obesity, glucose homeostasis, hypertension, and other physiological or
pathological processes.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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