Towards control of χ-space:: Conformationally constrained analogues of Phe, Tyr, Trp and His

Topographical changes alone can greatly affect the potency and selectivity of peptidic ligands. Though this approach to ligand design is in its infancy, significant progress has been made and some very impressive peptide-based ligands have been discovered. Conformationally constrained amino acids are important tools for the exploration of χ space. There is currently a variety of constrained analogues of Phe, Tyr, Trp and His available from routes based either on classical reactions combined with resolution procedures or on contemporary stereoselective methodology. These amino acids provide some degree of control over the orientation of the aromatic side-chains by restricting χ1 and/or χ2. There is, however, a need for a deeper understanding of the conformational properties of many of these amino acids, and for the design, synthesis and conformational analysis of novel amino acids with well-defined χ1 and χ2 angles. Given the importance of peptides in biological systems, it is predicted that constrained analogues of the proteinogenic amino acids will become increasingly important tools in structure-activity studies, and in the rational design of pharmaceutical products.