Enzymatic degradation of endomorphins.
Centrally acting plant opiates, such as morphine, are the most frequently used analgesics for the relief of severe pain, even though their undesired side effects are serious limitation to their usefulness. The search for new therapeutics that could replace morphine has been mainly focused on the development of peptide analogs or peptidomimetics with high selectivity for one receptor type and high bioavailability, that is good blood-brain barrier permeability and enzymatic stability. Drugs, in order to be effective, must be able to reach the target tissue and to remain metabolically stable to produce the desired effects. The study of naturally occurring peptides provides a rational and powerful approach in the design of peptide therapeutics. Endogenous opioid peptides, endomorphin-1 and endomorphin-2, are two potent and highly selective mu-opioid receptor agonists, discovered only a decade ago, which display potent analgesic activity. However, extensive studies on the possible use of endomorphins as analgesics instead of morphine met with failure due to their instability. This review deals with the recent investigations that allowed determine degradation pathways of endomorphins in vitro and in vivo and propose modifications that will lead to more stable analogs.
Janecka
Anna
A
Laboratory of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. ajanecka@zdn.am.lodz.pl
Staniszewska
Renata
R
Gach
Katarzyna
K
Fichna
Jakub
J
D000626:Aminopeptidases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D018826:CD13 Antigens / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004355:Drug Stability; D009842:Oligopeptides / Q000378:metabolism*; D018847:Opioid Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists*
D000701:Analgesics, Opioid; D009842:Oligopeptides; D018847:Opioid Peptides; D011480:Protease Inhibitors; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C105294:endomorphin 2; D000626:Aminopeptidases; D018826:CD13 Antigens; C022750:X-Pro aminopeptidase; D018819:Dipeptidyl Peptidase 4