Lipo-endomorphin-1 derivatives with systemic activity against neuropathic pain without producing constipation.
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.
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
Pegah
P
Varamini
Friederike M
FM
Mansfeld
Joanne T
JT
Blanchfield
Bruce D
BD
Wyse
Maree T
MT
Smith
Istvan
I
Toth
D000700:Analgesics / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D003248:Constipation / Q000139:chemically induced*; D004355:Drug Stability; D004361:Drug Tolerance; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy*; D009842:Oligopeptides / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D009270:Naloxone