Designing Molecules: Specific Peptides for Specific Receptors

Summary: Peptides are the largest class of mediators of intercellular communication in the central nervous system. These molecules pose special problems in design for potential medical applications because of the high degree of flexibility, lack of high receptor selectivity, and ready biodegra‐dation or clearance. The global and local use of conformational constraints has overcome these difficulties. Structure‐biological activity relationships, molecular modeling, conformational analysis, conformational calculations, and molecular dynamics simulations can all be used to derive suitable lead structures and conformational models. Often, a single, constrained peptide analogue can be designed, which will have many of the desired biological and biophysical properties, and will serve as a template. Peptide analogues with high potency, exquisite receptor selectivity, and biological stability can be obtained. The approach is illustrated by the design of cyclic enkephalin‐ago‐nist analogues with exceptional δ‐opioid‐receptor selectivity, and of constrained somatostatin analogues that have become opioid peptides and possess potent opioid antagonist activities and exceptional selectivity for μ‐opioid receptors.