Lipo-endomorphin-1 derivatives with systemic activity against neuropathic pain without producing constipation

• Published in: PloS one Vol. 7; no. 8; p. e41909
• Main Authors: Varamini, Pegah, Mansfeld, Friederike M, Blanchfield, Joanne T, Wyse, Bruce D, Smith, Maree T, Toth, Istvan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.08.2012; Public Library of Science (PLoS)
• Subjects: Acids; Amino acids; Analgesics; Analgesics - adverse effects; Analgesics - chemistry; Analgesics - metabolism; Analgesics - pharmacology; Analysis; Animals; Biology; Blood-brain barrier; Cell Line, Tumor; Cell Membrane Permeability; Chemistry; Constipation; Constipation - chemically induced; Derivatives; Drug Stability; Drug Tolerance; Endogenous opioids; Endomorphin-1; Humans; In vivo methods and tests; Intravenous administration; Lipid Metabolism; Male; Medicine; Membrane permeability; Metabolism; Morphine; N-Terminus; Naloxone; Naloxone - pharmacology; Narcotics; Nervous system; Neuralgia; Neuralgia - drug therapy; Neuropathy; Oligopeptides - adverse effects; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - pharmacology; Opioid receptors; Pain; Pain perception; Peptides; Permeability; Pharmacy; Plasma; Proteolysis; Rats; Rats, Sprague-Dawley; Receptors; Receptors, Opioid, mu - metabolism; Structure-Activity Relationship; Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041909

To enhance the drug-like properties of the endogenous opioid peptide endomorphin-1 (1 = Tyr-Pro-Trp-Phe-NH(2)), the N-terminus of the peptide was modified with 2-aminodecanoic acid, resulting in compound 3. Tyr in compound 1 was replaced with 2,6-dimethyltyrosine yielding compound 2. Derivative 2 was also substituted with 2-aminodecanoic acid producing compound, 4. Lipoamino acid-modified derivatives showed improved metabolic stability and membrane permeability while maintaining high μ-opioid (MOP) receptor binding affinity and acting as a potent agonist. In vivo studies showed dose-dependent antinociceptive activity following intravenous (i.v.) administration of compounds 3 and 4 in a chronic constriction injury (CCI)-rat model of neuropathic pain with ED(50) values of 1.22 (± 0.93) and 0.99 (± 0.89) µmol/kg, respectively. Pre-treatment of animals with naloxone hydrochloride significantly attenuated the anti-neuropathic effects of compound 3, confirming the key role of opioid receptors in mediating antinociception. In contrast to morphine, no significant constipation was produced following i.v. administration of compound 3 at 16 µmol/kg. Furthermore, following chronic administration of equi-potent doses of compound 3 and morphine to rats, there was less antinociceptive tolerance for compound 3 compared with morphine.