The penetration of the blood-brain barrier (BBB) by neurologically active peptides has remained an enigmatic problem for many decades. Studies have shown that glycosylation of small peptides (enkephalins) leads to glycopeptides that are more stable, and which penetrate the BBB in pharmacologically useful amounts. Mechanistic studies have shown that endocytosis at the endothelial layer of the brain capillaries is responsible for transport. Recent studies indicate that much larger peptides (endorphins) are capable of adopting helical conformations in the presence of membranes, and are also transported across the BBB. This proposal seeks to explore and exploit the transport and pharmacology of glycosylated dynorphin and endorphin peptides, and to evaluate them as candidates for the treatment of chronic pain. A unique group of investigators has been assembled in order to bring synthetic organic, biophysical, and pharmacological tools to bear on this problem. Solution and solid phase NMR techniques will examine the effects of glycopeptide adsorption to membrane models, seeking to understand the effects on glycopeptide conformation, as well perturbations of the membrane during adsorption. Data from these studies will be correlated with glycopeptide stability, transport rates, and binding affinities. Finally, behavioral studies in mice will be carried out to test the effects of systematic administration of these drugs in models of inflammatory and neuropathic pain, opioid-mediated side effect (Gl transit, tolerance/dependence, etc.) and anxiety/depression. Based on our previous research and published papers on delta receptors, we predict that some of the compounds will have better efficacy, reduced toxicity and/or improved side effect profiles compared to morphine-like analgesics. More importantly, the central hypothesis (that glycosylation strategies can be applied to larger peptides to increase CNS bioavailability) will be rigorously tested using a multidisciplinary approach. If the hypothesis is supported, the technology may lead to a sea-changing platform technology on which to base the clinical development of diverse pharmaceuticals based on endogenous neuropeptides.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-C (91))
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Bosetti, Francesca
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University of Arizona
Schools of Arts and Sciences
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Flores, Andrew J; Bartlett, Mitchell J; Root, Brandon K et al. (2018) The combination of the opioid glycopeptide MMP-2200 and a NMDA receptor antagonist reduced l-DOPA-induced dyskinesia and MMP-2200 by itself reduced dopamine receptor 2-like agonist-induced dyskinesia. Neuropharmacology 141:260-271
Lefever, Mark; Li, Yingxue; Anglin, Bobbi et al. (2015) Structural Requirements for CNS Active Opioid Glycopeptides. J Med Chem 58:5728-41
Li, Yingxue; St Louis, Lindsay; Knapp, Brian I et al. (2014) Can amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to ?-endorphin? J Med Chem 57:2237-46
Li, Yingxue; Lefever, Mark R; Muthu, Dhanasekaran et al. (2012) Opioid glycopeptide analgesics derived from endogenous enkephalins and endorphins. Future Med Chem 4:205-26
Mabrouk, Omar S; Falk, Torsten; Sherman, Scott J et al. (2012) CNS penetration of the opioid glycopeptide MMP-2200: a microdialysis study. Neurosci Lett 531:99-103
Lefever, Mark R; Szabo, Lajos Z; Anglin, Bobbi et al. (2012) Glycosylation of ýý-amino acids by sugar acetate donors with InBr3. Minimally competent Lewis acids. Carbohydr Res 351:121-5
Ezzili, Cyrine; Mileni, Mauro; McGlinchey, Nicholas et al. (2011) Reversible competitive ýý-ketoheterocycle inhibitors of fatty acid amide hydrolase containing additional conformational constraints in the acyl side chain: orally active, long-acting analgesics. J Med Chem 54:2805-22
Yeomans, Larisa; Muthu, Dhanasekaran; Lowery, John J et al. (2011) Phosphorylation of enkephalins: NMR and CD studies in aqueous and membrane-mimicking environments. Chem Biol Drug Des 78:749-56
Yue, Xu; Falk, Torsten; Zuniga, Leslie A et al. (2011) Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease. Brain Res 1413:72-83
Do Carmo, Gail Pereira; Polt, Robin; Bilsky, Edward J et al. (2008) Behavioral pharmacology of the mu/delta opioid glycopeptide MMP2200 in rhesus monkeys. J Pharmacol Exp Ther 326:939-48

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