Design and Activity Estimation of a New Class of Analgesics

Abstract

Our ability to use rational design for the generation of useful peptides is depends on our ability to determine the specific relationships of molecular structure to biological activity. Opiates and opioid peptides display a large spectrum of biological activities, including analgesia, respiratory depression, euphoria, hypothermia, tolerance, physical dependence etc. There are at least three different receptor classes ( μ, δ, κ ) differing from one another in their structural requirements towards opioid ligands. In order to associate a particular receptor class with a distinct biological function, it is of great importance to develop opioid receptor ligands with high activity and selectivity for a particular receptor type. Unfortunately, none of the endogenous opioid peptide is very selective for a particular receptor class. The lack of selectivity observed with most naturally occurring opioid peptides and with many of their linear analogs is most likely due to their structural flexibility which permits conformational adaptation to more than one opioid receptor type. Flexible molecules of peptides assume many conformations in solution. One of the available conformation or closely related family of conformations is responsible for the biological activity of the peptide. To determine which conformations are important it is necessary to confine conformational space accessible to flexible peptides. The most drastic restriction of the overall conformation freedom can be achieved through peptide cyclization^1,2. Cyclization through covalent linkage of two side-chains has been performed by disulfide bond formation or by amide bond formation. In particular, cyclization of enkephalin via side chains of appropriately substituted amino acid residues have been successful ^3–9.