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sequence (discussed above) support a hypothesis that the DTic is exo ring flipped in the receptor-bound
state.
There are two factors that must be considered when applying structure-activity-relationship (SAR)
information from a series of peptides toward the design of nonpeptide mimetics and putative library
scaffolds. One is in regard to the backbone conformation that primarily serves as a structural scaffold
upon which the various functionalities (side chains) are attached. The other factor is the side chains
themselves whose spatial positions are primarily dictated by the backbone structure. Usually, the threedimensional
arrangement of these differing chemical groups are responsible for affinity and triggering of
the receptor. Knowledge of the relative importance of the individual side chains and amide bonds for
receptor affinity is therefore a critical aspect of small molecule design from a peptidic structure-activity
relationship.
Conformationally constrained derivatives of HOE 140 have been prepared in continuing efforts to
elucidate the ideal backbone conformation peptide antagonists must adopt for bradykinin B2 receptor
interaction. One such series made use of Cα- or N-methyl substituted amino acids, incorporated at
position(s) Gly4, Phe5, or both, in the peptide D-Arg0-Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-D-Tic7-Oic8-Arg9 (NPC 18545) [34]. An N-methyl substitution in the backbone of an L-amino acid is known to disfavor
helical, or twisted, backbone conformations while favoring an extended backbone. The contrasting Cα methyl modification tends to favor a helical (twisted), rather than extended, conformation [35,36]. These
conformational preferences apply only to the backbone φ, ψ angles (where φi and ψi correspond to
backbone dihedral angles for residue i, defined by the four adjacent amino acid backbone atoms C i-1-N i-
Cαi-Ci band Ni-Cαi-Ci-Ni+1, respectively) of the amino-acid residues bearing the modification. Receptor
binding assays were performed in membrane preparations of the guinea pig ileum, a source of B2
receptors, wherein these constrained peptides were evaluated for their abilities to compete with
bradykinin binding.
With the exception of the C α-methyl-Phe 5-containing peptide (NPC 18540), each conformational
constraint caused a significant, at least 1000-fold, loss in binding affinity with respect to the
unconstrained parent peptide, NPC 18545. There are several factors that could contribute to the poor
receptor affinities measured for these peptides. In addition to the possible induction of an adverse
conformation via the N-methyl substitution, this modification also eliminates an amide proton that might
be an important hydrogen-bond donor during ligand-receptor interaction. Furthermore, the N-methyl
substitution enhances the likelihood of trans-cis amide bond isomerization, which could also disrupt an
optimal ligand-receptor interaction by altering the spatial display of the local side chains. The C α-methyl-
Phe 5 substitution of NPC 18540 is well
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