Recent statistics from the World Health Organization indicate that a high percentage
of people worldwide suffer from a wide variety of acute or cancer-associated chronic
pain. At present, with a few exceptions, the treatment of severe pain relies upon
oral administration of the mu-opioid receptor-targeting opiate morphine and its surrogates
under strict clinical control. In spite of the powerful in vivo efficacy of these
drugs, their long-term use is limited by antinociceptive tolerance, physical dependence,
and respiratory depression that evolve. As no analgesics with moderate side effect
profiles are currently available for the therapy of different types of pain and stages
of cancer, considerable efforts must be made in the search for opiate substitutes.
Following the recognition that endogenous peptide ligands of the opioid receptors
exert striking effects in various pain models, and with the recent advances in chemical
synthesis methods, research interest has steadily moved toward peptide-based compounds
as potential opioid analgesics. The endomorphins are an attractive set of endogenous
opioid peptides that may meet the requirements of opioid-based pain management. By
virtue of their excellent mu-opioid receptor labeling and favorable analgesic properties,
these tetrapeptides have gained attention in recent years as potential lead compounds.
The ever-increasing number of publications in this field strongly suggests that modified
analogues of endomorphins could serve as potent substitutes for opiates, with a lower
propensity to induce side effects. This review surveys the main results achieved over
the past decade regarding the design, radiolabeling, pharmacological characterization,
and structure-activity features of a large body of endomorphin derivatives.