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Document Figure 3 Receptor binding curves for the binding of NPC 17410 and NPC 17643 to B2 receptors from the guinea pig ileum and cloned rat and human B2 receptors. Legends are noted on the figure. turn, there appears to be some type of steric interference (or lack of a pocket) that might otherwise accommodate the ethers of the cis configuration. Page 126 More recently, bradykinin B2 receptors have been cloned from both rat and human sources [27,28]. In receptor-binding experiments using these new receptors, selected members of the DHype-containing decapeptides were used to probe these receptors [24], a representative sample of the data is shown in Figure 3. Specifically, NPC 17643 (a trans propyl ether of D-4-hydroxyproline at position 7) and NPC 17410 (a cis propyl ether of D-4-hydroxyproline at position 7) were used. Although the trans ethercontaining decapeptide behaved similarly in binding assays directed toward the bradykinin B2 receptors in guinea pig, rat, and human, the cis ether-containing decapeptide, NPC 17410, displayed an interesting pharmacology. In particular, NPC 17410 bound with similar affinity to both the guinea pig and rat bradykinin B2 receptors, but had an appreciably higher affinity for the human B2 receptor. This result strongly suggests that there are slight structural differences in the antagonist binding sites of the rat and human B2 receptors. With clones available for the rat and human bradykinin B2 receptors, this prompted a systematic search using NPC 17410 binding to rat/human bradykinin B2 receptor chimeras and point mutations in an attempt to discover residues on the receptor that comprise this antagonist site. The details and results of the subsequent application of these novel receptor-probing ligands is fully described later in this chapter. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_126.html [4/5/2004 4:58:51 PM]
Document Page 127 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 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_127.html [4/5/2004 4:58:53 PM]
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Document dine) and didanosine (dide
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Page 113 and 114: Document Page 88 transfer (Figure 3
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Page 137 and 138: Document when metals are bound. Fin
Page 139 and 140: Document cubation of phosphotyrosin
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Page 149 and 150: Document 4 Bradykinin Receptor Anta
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Page 171 and 172: Document Page 141 receptor with int
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Document III. Results and Discussio
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Document 17 Structure and Functiona
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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