title: Peripherally acting novel lipo-endomorphin-1 peptides in neuropathic pain without producing constipation.
abstract: We previously described two novel analogues of endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, 1), modified with an 8-carbon lipoamino acid (C8LAA) with or without replacement of Tyr(1) with 2,6-dimethyltyrosine (Dmt) at the N-terminus of the peptide (compounds 3 and 4, respectively). They were shown to be more stable and permeable, and acted as potent μ-opioid receptor agonists. In this study we report that the C8LAA modification resulted in successful systemic delivery of both analogues. They produced potent dose-dependent pain relief in a chronic constriction injury-rat model of neuropathic pain after intravenous administration with ED50 values obtained at 6.58 (±1.22) μmol/kg for 3 and 6.18 (±1.17) μmol/kg for 4. Using two different rat models of constipation that assess the effects of μ-opioid receptor agonists on stool hydration and gastro-intestinal motility, compound 3 produced insignificant constipation at 16 μmol/kg, whereas morphine elicited significant constipation at 2 μmol/kg. Compound 3 in contrast to morphine, did not attenuate the hypercapnic ventilatory response at 5 μmol/kg, a dose that fully alleviated hindpaw sensitivity at the time of peak effect in CCI-rats. This finding revealed the lack of respiratory depression effect at antinociceptive dose.
authors: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: Pegah
authors: P
authors: Varamini
authors: Wei Huang
authors: WH
authors: Goh
authors: Friederike M
authors: FM
authors: Mansfeld
authors: Joanne T
authors: JT
authors: Blanchfield
authors: Bruce D
authors: BD
authors: Wyse
authors: Maree T
authors: MT
authors: Smith
authors: Istvan
authors: I
authors: Toth
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D003248:Constipation / Q000139:chemically induced*; D005769:Gastrointestinal Motility / Q000187:drug effects; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D009842:Oligopeptides / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012119:Respiration / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1