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subsequently been successfully applied toward the design and synthesis of several nopeptide scaffolds
and mimetics. Ultimately these mimetics were assembled in a combinatorial fashion as discussed in
Section IV.
Page 130
In a related study, wherein NPC 18149 (DArg 0-Arg 1-Gly 2-Gly 3-Gly 4-Phe 5-Ser 6-DTic 7-Oic 8-Arg 9; K i =
13.7 nM; Guinea pig ileum) was taken as the lead peptide, the relative contributions to binding affinity
from each amide bond in the segment Arg 1-Gly 2-Gly 3-Gly 4-Phe 5 were examined. Aminovaleric acid was
used in a systematic fashion as a surrogate for any pair of adjacent Gly-Gly residues in the peptide.
Aminovaleric acid is atomically identical to Gly-Gly with the exception that the amide bond linking the
two glycines is replaced by two methylenes. The synthesis of Gly 4-Phe 5 required a special Gly-Phe
mimic that has since been reported [39]. Since this substitution introduces flexibility into the peptide, it
is a means of probing the structural role a given amide bond plays during receptor interaction. Potential
hydrogen-bond donor and acceptor groups in the amide bond are removed via this substitution, which
yields additional insights into potential electrostatic interactions that may also be important during
ligand-receptor interactions.
The conclusions drawn from the data are that in terms of structural or electrostatic interactions with this
antagonist site on the receptor, the amide bond linking residues two and three may not be as critical as
those linking residues three to four and four to five.
Each of these investigations was aimed toward an understanding of either the backbone conformation of
this prototypical decapeptide or the relative importance of the functional groups in the side chains that
make significant contributions to receptor affinity. From the former, nonpeptide frameworks and
scaffolds can be imagined. From the latter, insights into which functionality is required for high-affinity
binding is derived. The remaining challenge is to reassemble these fragments onto synthetically feasible
nonpeptide frameworks as potential new lead compounds. Our approach toward addressing this
challenging problem is described later in this chapter.
III. Receptor Structure-Based Investigations
A. Elucidation of an Agonist Binding Site on the B2 Receptor
In addition to the deductions one might make about a receptor binding site on the basis of receptor
binding data from conformationally constrained ligands as previously described, models of bradykinin
and bradykinin antagonists bound to their respective sites on the receptor as complimentary aspects of
the overall strategy are also valuable. Unfortunately, due to the nature of the bradykinin
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