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Opioid peptides and peptidomimetics
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Ping He
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Much of our research emphasizes the design and synthesis of conformationally restricted analogs of native peptides, especially of the ligands for delta, mu, kappa-opioid and orphanin (ORL1) receptors, to increase their affinity and pharmacological selectivity. The rationale for the approach is that less flexible peptides may exhibit preferred interactions with one of a set of receptor subtypes leading to increased selectivity. The conformational analyses of these ligands utilize both experimental (NMR) and theoretical approaches (conformational search/molecular mechanics) to arrive at a pharmacophore model. The model generated is then employed as a template for the design of new analogs with improved bioactivity.
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delta-opioid agonist JOM-13: pharmacophore model
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The models of bioactive conformations for the delta-opioid and mu-opioid receptors were elucidated from two series of structurally related tetrapeptides: analogs of JOM-13 for delta and of JOM-6 for mu-receptors. The pharmacophore model for JOM-13 is very similar to the crystal structure of the peptide.
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JOM-13: X-ray structures (model is shown by thin line)
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The results of peptide SAR studies and results from mutagenesis of opioid receptors indicate that the ligand-receptor interactions suggested from the modeling are sufficiently precise to allow structure based drug design. In particular, we are designing structurally related ligands with optimized selectivity not only for mu, delta, but also for kappa and orphanin (ORL1) receptors by exploiting specific structural differences among these receptors and regions of the ligand binding sites.
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JOM-6: pharmacophore model
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Peptides, in general, have two liabilities that make them undesirable candidates for drugs. First, they are typically enzymatically labile and, second, they are often too large for good bioavailability. To circumvent these liabilities we are pursuing the design and synthesis of peptidomimetics, which maintain the key elements required for activity but which replace the labile peptide bonds with more stable features and which are stripped of unessential structural components.
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mu-receptor selective peptidomimetic
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Related Publications
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McFadyen IJ, Sobczyk-Kojiro K, Schaefer MJ, Ho JC, Omnaas JR, Mosberg HI, Traynor JR
Tetrapeptide derivatives of [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE) lacking an N-terminal tyrosine residue are agonists at the mu-opioid receptor.
Pharmacol. Exp. Ther., 295: 960-966 (2000)
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Mosberg HI
Complementarity of delta opioid ligand pharmacophore and receptor models.
Biopolymers, 51: 426-39 (1999)
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McFadyen IJ, Ho JC, Mosberg HI, Traynor JR
Modifications of the cyclic mu receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]NH2 (Et): effects on opioid receptor binding and activation.
J. Pept. Res., 55: 255-261 (2000)
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Wang C, McFadyen IJ, Traynor JR, Mosberg HI
Design of a high affinity peptidomimetic opioid agonist from peptide pharmacophore models.
Bioorg. Med. Chem. Lett., 8: 2685-2688 (1998)
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Ko MC, Lee H, Song MS, Sobczyk-Kojiro K, Mosberg HI, Kishioka S, Woods JH, Naughton NN
Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys.
J. Pharmacol. Exp. Ther., 305: 173-179 (2003)
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External Funding
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DA 03910, H. I. Mosberg, PI
NIH/NIDA
Conformation-Selectivity Relations of Opioid Peptides
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