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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
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