We propose to develop novel opioid peptide analogs and derivatives with minimal side effects for use in obstetric analgesia. The structural characteristics of the new compounds should be such that they (i) retain high selectivity for either mu or delta opioid receptors, (ii) are able to penetrate the blood-brain barrier (BBB) (systemic administration) or the dura mater (epidural administration), and (iii) cannot cross the placental barrier (PB). It is expected that analgesics with this kind of profile may be discovered through structural modifications that produce considerable variation in the physico-chemical properties of already existing, receptor-selective opioid peptides. As parent peptides we will use four mu-selective opioid tetra-and dipeptide agonists and two novel dipeptide delta agonists, all of which were recently developed in the P.I.'s laboratory. We intend to achieve better penetration of the BBB by rendering the peptides more lipophilic (passage via passive diffusion) or by increasing the number of positive charges they carry (passage via non- specific, absorptive endocytosis). It is expected that a certain degree of lipophilicity and/or a certain number and distribution of positive charges may enable a peptide analog to cross the BBB but not the PB. Lipophilicity will be enhanced through incorporation of highly hydrophobic, artificial amino acids into the peptide and/or attachment of lipophilic moieties to end groups, whereas positive charges will be introduced through N- or C- terminal extension with basic amino acids and/or through peptide bond reductions or reversals. The opioid receptor affinities and selectivities of the new analogs will be determined in binding assays based on displacement of mu-, delta- and k-selective radio-ligands from rat brain or guinea pig membrane binding sites. Opioid agonist contractions of the guinea pig ileum and of the vase deferentia of the mouse, rat, hamster and rabbit. The relative stability of the analogs against enzymatic degradation (rat brain peptidases) will be examined. Analgesic activities of the compounds will be determined in the mouse writhing assay, a test model permitting the detection of both peripheral and central atinocipeption, and in the mouse hot plate test which detects only centrally mediated analgesic effects. Promising compounds will be synthesized on a larger scale for pharmacological and pharmacokinetic studies using chronically-instrumented pregnant sheep model to be carried out in Dr. Szeto's laboratory. The same compounds will also be prepared in deuterated form as standards for quantitative MS analyses to be performed in Dr. Desiderio's laboratory.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Weill Medical College of Cornell University
New York
United States
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Szeto, H H; Birk, A V (2014) Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther 96:672-83
Shimoyama, Megumi; Schiller, Peter W; Shimoyama, Naohito et al. (2012) Superior analgesic effect of H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA), a multifunctional opioid peptide, compared to morphine in a rat model of neuropathic pain. Chem Biol Drug Des 80:771-4
Han, Zhaosheng; Varadharaj, Saradhadevi; Giedt, Randy J et al. (2009) Mitochondria-derived reactive oxygen species mediate heme oxygenase-1 expression in sheared endothelial cells. J Pharmacol Exp Ther 329:94-101
Yang, Lichuan; Zhao, Kesheng; Calingasan, Noel Y et al. (2009) Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Antioxid Redox Signal 11:2095-104
Shimoyama, Megumi; Szeto, Hazel H; Schiller, Peter W et al. (2009) Differential analgesic effects of a mu-opioid peptide, [Dmt(1)]DALDA, and morphine. Pharmacology 83:33-7
Fichna, Jakub; do-Rego, Jean-Claude; Chung, Nga N et al. (2008) [Dmt1, d-1-Nal3]morphiceptin, a novel opioid peptide analog with high analgesic activity. Peptides 29:633-8
Szeto, Hazel H (2008) Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases. Ann N Y Acad Sci 1147:112-21
Fichna, Jakub; do-Rego, Jean-Claude; Janecki, Tomasz et al. (2008) Novel highly potent mu-opioid receptor antagonist based on endomorphin-2 structure. Bioorg Med Chem Lett 18:1350-3
Mizuguchi, Yasunori; Chen, Jie; Seshan, Surya V et al. (2008) A novel cell-permeable antioxidant peptide decreases renal tubular apoptosis and damage in unilateral ureteral obstruction. Am J Physiol Renal Physiol 295:F1545-53
Szeto, Hazel H (2008) Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal 10:601-19

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