Indirect-acting strategy of opioid action instead of direct receptor activation: dual-acting enkephalinase inhibitors (DENKIs).

Abstract

Although pain is one of the most common afflictions, it is often inadequately managed because the available analgesic options are relatively limited due to insufficient efficacy, unacceptable adverse effects or the potential for misuse or abuse. However, recent publications suggest that an alternative approach-indirect enhancement of endogenous pain-relieving pathways-might be desirable. We review this approach, in particular the dual enkephalinase inhibitors (DENKIs). Published literature and Internet sources were searched for information related to the basic science and clinical data on inhibition of metabolic pathways of endogenous analgesic agents. The identified sources were reviewed, assessed and synthesized. Emphasis was placed on the benefits of the approach, as well as on the individual agents. Inhibition of the enzymes that degrade the endogenous opioid ligands Met- and Leu-enkephalin results in an increased synaptic concentration of the enkephalins and an analgesic effect in a variety of animal models of pain and in preliminary trials in humans. The design of compounds that inhibit both of the two major enkephalin-degrading enzymes (neprilysin and aminopeptidase N) has been found to be better than those that inhibit only one of the enzymes. These dual-acting enkephalinase inhibitors yield analgesia with less adverse effects than current opioid drugs. Unlike currently available analgesics, inhibitors of the metabolic degradation of endogenous analgesic substances attempt to elicit a more "natural" and targeted analgesic effect. This indirect approach offers an opportunity for novel additions to the otherwise relatively limited choice of analgesic classes.