Cyclic Aromatic Amino Acids with Constrained 1 and 2 Dihedral Angles

The concept of topographic design of peptide neurotransmitters and hormones was pioneered by Hruby ( 1 , 2 ). When the design involved primarily constraint of the side chains of a peptide that has a well-defined backbone conformation, the term “topographic design on a stable template” was proposed ( 3 ). The side chain χ 1 of aromatic amino acids, such as Phe, Trp, Tyr, and His, can be constrained in either the gauche (−) or gauche (+) conformation by linking the nitrogen atom to the aromatic ring through a methylene bridge (Fig. 1 ).   Fig. 1.  Principle of side-chain constraint for Phe, Trp, and His.