Chapter 4. Analgesics, Endorphins, and the Opiate Receptor

Abstract

While the occurrence of the Met-enkephalin sequence at the N-terminus of β-endorphin indicates a biosynthetic origin of Met-enkephalin, the lack of identification of an analogous Leu–enkephalin precursor implies that the endorphin system is complex. The structure of dynorphin, a novel pituitary endorphin, is particularly interesting as the Leu-enkephalin C-terminus is followed by an Arg–Arg sequence, potentially allowing facile release of Leu–enkephalin. The endorphin system has appzared to become more and more complex since the discovery of the enkephalins in 1975. Transfers of (3H)-cerebroside sulfate (CS), used as a model receptor, and their inhibitions by various antagonists, correlated closely with their analgetic potencies in man, suggest a similarity between opiate–CS and opiate–receptor interactions. The drug–CS complexes appear to be of two types, hydrophobic and hydrophilic, and it is proposed that the hydrophilicity of the drug–CS complex is associated with degree of hydration rather than ionic bond strength. The role of the phenolic group in opiate receptor binding and antinociception has been examined in a series of morphine derivatives. The N-(2–cyanoethyl) moiety substituted in various classes of opioids causes paradoxical pharmacological effects.