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The des-Arg 9 forms of these peptides have also been shown to have high affinity for the recently cloned
human B1 receptor [24]. An extension of the work described herein would be to use a more complete
series of des-Arg 9 DHype-containing nonapeptides to probe the binding site of this new receptor where
other interesting pharmacological differences are likely to exist since the B1 receptor is only 33%
homologous to the human B2 [29].
In summary, the DHype-containing decapeptides have been useful in many regards. First, they
incorporate a novel β-turn mimetic that was alternatively functionalized and used to probe the unknown
topology of the guinea pig, rat, and human bradykinin B2 receptors. In this role, one of these tools
showed differential pharmacology between rat and human forms of the receptor. This tool was used in a
synergistic fashion with subsequent molecular biological and computational procedures in the
elucidation of an antagonist binding site. Second, these peptides, together with another potent
decapeptide antagonist with similar conformational constraints [30,31], provide the first strong
experimental evidence that high-affinity decapeptide bradykinin receptor antagonists adopt a C-terminal
β turn in the receptor-bound conformation. Third, certain members of this series of decapeptides contain
alkyl ethers of D-4-hydroxyproline at position seven. In this regard, they are the very first examples of
decapeptide bradykinin receptor antagonists that do not contain a D-aromatic amino acid at the seventh
position as had been previously deemed to be essential. Commercially, this renders the series patentably
distinct from all other known bradykinin receptor antagonists. Finally, several members of the series
(i.e., NPC 17731, NPC 17761, NPC 17974) are among the most potent antagonists for this receptor yet
reported. Hence, there may be applications for these compounds as human therapeutics.
Several “second generation” decapeptide antagonists have been reported, but the prototype from the
class, which was first to be reported, is HOE 140 (DArg0-Arg1-Pro2-Hyp3-Gly4-Thi5-Ser6-DTic7-Oic8- Arg9) [30,31]. This decapeptide has also been shown to preferentially adopt a C-terminal β turn,
consistent with the previous discussion [26,32,33]. The side chain of DTic at position seven is, however,
flexible. While side-chain rotational movement is not allowed, the saturated six-membered ring easily
undergoes an endo/exo ring-flipping motion. Hence, the β turn predominates about the backbone
dihedral angles, but the side chain of DTic could be either endo or exo ring flipped in the receptor-bound
conformation. In the absence of an appropriate x-ray crystallographic structure, there is no definitive
means of establishing which possibility is correct. This type of ring-flipping conformational change
serves to orient the bulky hydrophobic side chain of the DTic residue to either one side of the β turn, or
the other. The data collected from the decapeptides containing either cis or trans ethers of D-4hydroxyproline
at the analogous position in the
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