Opiate alkaloids, such as
morphine, are powerful
analgesic agents that are the drugs of choice for the treatment of severe
pain. The pharmacological effects of
opiates are mediated through the binding and activation of membrane-bound
opioid receptors that are found in the central and peripheral nervous systems.
Opioid receptors have been classified into three different types, mu, delta and kappa, and are activated by the specific
ligands. It has been demonstrated that the most potent antinociceptive effects are mediated by the
mu-receptor. However, until 1997 no endogenous
ligand for this receptor was known. The identification of endomorphins opened a new era in the research of the mu-
opioid system. They are the first reported brain
peptides that label
mu-receptor with high affinity and selectivity and therefore are proposed as the endogenous
mu-opioid receptor ligands.
Morphine and endomorphins act as agonists at the same
mu-opioid receptor, but the latter are thought to inhibit
pain without some of the undesired side-effects of plant
opiates. This observation encouraged extensive studies on the possible use of endomorphin analogs as
analgesics instead of
morphine. This review summarizes a decade of research on structure-activity relationship studies of endomorphin analogs, aimed at obtaining compounds with increased bioavailability, in particular with better barrier penetration and resistance against enzymatic degradation. Chemical modifications that led to obtaining potent and selective agonists and antagonists based on the structure of endomorphins are discussed.