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Document Figure 7 Schematic of the primary amino sequence of the human B2 receptor. Shown in black are residues experimentally identified as contributing to an agonist binding site. The dark gray residues are suspect positions for contributing to an antagonist site. The residues colored light gray have been mutagenized only in the rat B2 receptor, but they are conserved in the human. The Thr 263 rarrow.gif Ala mutation interferes with agonist binding only, while Gln 260 partially interferes with agonist and first generation antagonist binding. Page 140 within the context of these TM6 residues. Currently, we have prepared these mutant receptors, but at this time binding to NPC 17410 remains unfinished. A summary of the amino acids in the human B2 receptor implicated in comprising either agonist or antagonist sites are highlighted in Figure 7. Marked in dark black are the residues of extracellular loop 3, TM 6, and the extracellular N-terminal segment that have been shown to participate in agonist binding. Marked in dark gray in TM 6 and TM 3 are residues likely to partially comprise an antagonist binding site based primarily on the chimeric receptor studies described previously, although there is no explicit experimental evidence as yet. Shown in light gray are two residues that are conserved between rat and human B2 receptors. Mutagenesis experiments have been done on this pair in the rat B2 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_140.html (1 of 2) [4/5/2004 5:00:06 PM]
Document Page 141 receptor with interesting results [54]. Mutations in Thr 263 only affect agonist binding, not antagonist. Mutations in Gln 260 affect binding of bradykinin and first generation antagonist peptides. As depicted in the figure, it is possible that the agonist and antagonist binding sites have domains on opposite sides of the helix that makes up TM 6, with Gln 260 being situated partly in both. IV. Design and Combinatorial Synthesis of Nonpeptidic Antagonists As was previously described, a significant body of information was generated that provides insights into the key structural features of bradykinin receptor binding sites and the residues that participate in ligand binding. In addition, from the ligand-based studies, knowledge about relevant structure-activity relationships was acquired. Our modular synthetic strategy was based primarily upon the recognition that high-affinity ligands appear to be comprised of three domains. These domains are (1) a positively charged N-terminal segment, (2) a midsection containing a bend or twist with some hydrophobic substituent attached and, (3) a C-terminal segment of appropriate hydrophobicity and structurally simulating a type II' β turn. Models of potent cyclic and linear peptide bradykinin receptor antagonists (described previously) were used in a comparative fashion to select nonpeptide ring systems from a database of chemical structures fine chemicals database. For each, some degree of chemical diversity was achieved by altering one of several parameters including, o, m, or p substitution of an aromatic ring or nature of alkyl substituent(s) as well as point(s) of synthetic attachment [55,56]. Each nonpeptide fragment was designed within the framework of several criterion. First, a given scaffold must closely match the known SAR and be compatible with the putative ligand binding site structure. Second, each scaffold must be a relatively simple synthetic target, having readily available starting material, no chiral centers and having a total synthesis of not more than 4–5 steps. Finally, each template must have a “C-terminal” carboxylate and an “N-terminal” amino group with no interfering functionality such that it could be readily used in a solid phase synthetic strategy. Given that each nonpeptide we identified was a viable surrogate for either the second or third domain of high-affinity ligands (as described above) our goal was to rapidly explore the receptor affinities of all possible combinations of these nonpeptide templates at position X and Y of the sequence DArg-Arg-X-Y-Arg, hence a combinatorial synthetic approach was taken. In this study, there were four linear aminoalkanoic acids [50], four different cinnamic acids, three different carbolines, three different phenanthridinones, and five different spirocyclics. The variability in the phenanthridinione series http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_141.html [4/5/2004 5:00:07 PM]
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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 197 and 198: Document IV. Drug Design Progressio
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Page 201 and 202: Document Table 1 Inhibition Data fo
Page 203 and 204: Document Page 166 As predicated, th
Page 205 and 206: Document References 1. Parks RE Jr.
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Page 209 and 210: Document 6 Structural Implications
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document II. Type IFNs A great deal
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Document D ddI, 152 tumour necrosis
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