Engineering endomorphin drugs: state of the art.
BACKGROUND
Although endomorphins-1 (EM-1; H-Tyr-Pro-Phe-Trp-NH(2)) and -2 (EM-2; H-Tyr-Pro-Phe-Phe-NH(2)) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties, suitable for application to health-related topics. While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimentally delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability; formation of MOR antagonists or mixed and dual μ/δ-acting ligands could find considerable therapeutic potential.


METHODS
This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand.


CONCLUSIONS
Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high-caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction.
National Institute of Environmental Health Sciences, Laboratory of Toxicology and Pharmacology, 111 South TW Alexander Drive, Research Triangle Park, NC 27709, USA. lazarus@niehs.nih.gov
Lawrence H
LH
Lazarus
Yoshio
Y
Okada
D000818:Animals; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008024:Ligands; D009842:Oligopeptides / Q000494:pharmacology*; D010330:Patents as Topic; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000503:physiopathology
D008024:Ligands; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C105294:endomorphin 2