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Design and synthesis of biologically active opioid peptides and peptidomimetics
Anthony F. Nastase , Katarzyna Sobczyk-Kojiro , Sean P. Henry , Deanna Montgomery
Conformationally restricted peptide ligands

Much of our research emphasizes structure based design and synthesis of analogs of native peptides, especially ligands for the delta (DOR), mu (MOR), and kappa (KOR)-opioid receptors and the related orphanin (ORL1) receptor. Our approach is to use our accurate receptor models, coupled with our previous, extensive structure-activity results, to design analogs with predictable selectivity and efficacy for specific receptor subtypes. For the analogs themselves, we focus on conformationally restricted peptides since these less flexible peptides may exhibit preferred interactions with one of a set of receptor subtypes leading to increased selectivity. Of particular interest to us is the use of similar cyclic peptide scaffolds while altering the attached side chains to selectively exploit structural differences in the binding sites of the opioid receptor subtypes.

delta-opioid agonist JOM-13: pharmacophore model



JOM-13: X-ray structures (model is shown by thin line)


An example of this approach is illustrated in Figure 1, which shows the binding conformations of the DOR selective peptide JOM-13 (bound to DOR) and the closely related, MOR selective peptide JOM-6 (bound to MOR). These two peptides, which differ only in the size of the tri-peptide cycle and in the nature of the C-terminus, display a 6000-fold shift in DOR v. MOR selectivity. The bioactive conformations of these peptides were elucidated by correlating the activities of a large set of conformationally constrained analogs with the conformational space available to these analogs. The resulting models have been shown to be consistent with our receptor models, indicating that the docked receptor/ligand complexes can be used for the design of new analogs with prescribed activity profiles. In particular, we are designing structurally related ligands with optimized selectivity not only for MOR and DOR, but also for KOR and orphanin (ORL1) receptors by exploiting specific structural differences among these receptors and regions of the ligand binding sites.

JOM-6: pharmacophore model


Peptidomimetics

As suggested above, elucidating the precise details governing ligand-receptor interactions and those underlying selectivity and efficacy requires an iterative process of analog design, synthesis, and testing, coupled with construction and validation of receptor and receptor-ligand interaction models. Peptide ligands are particularly amenable for this process since they allow a wide range of synthetically accessible structural diversity. However, peptides, in general, have two liabilities that make them less desirable candidates for drugs. First, they are typically enzymatically labile and, second, they are often too large for good bioavailability. Therefore our efforts are directed towards synthesizing ligands that are more resistant to proteolytic degradation, have superior bioavailablity (higher hydrophobicity, low molecular weight), and can be tailored to achieve desired selectivity, efficacy, and potency. Currently 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. These peptidomimetics represent more ‘druggable’ targets in the search for novel, selective opioid ligands. One example from our lab is shown in Figure 2. This compound displays very high affinity for MOR and serves as the starting point for a series of planned analogs designed for improved selectivity and potency.

mu-receptor selective peptidomimetic




Related Publications

Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, Mosberg HI, Folk JE, Rice KC, Watson SJ, Woods JH
Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects.
Eur J Pharmacol., 531: 151-159 (2006)

Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson SJ, Woods JH
Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats.
Brain Res., 1069: 172-181 (2006)

Przydzial MJ, Pogozheva ID, Ho JC, Tharp TA, Drankhan KE, Sawyer E, Traynor JR, Mosberg HI
Design of high affinity cyclic pentapeptide ligands for kappa-opioid receptors.
J. Pept. Res., 66: 255-262 (2005)

Przydzial MJ, Pogozheva ID, Bosse KE, Andrews SM, Tod A, Tharp TA, Traynor JR, Mosberg HI
Roles of residues 3 and 4 in cyclic tetrapeptide ligand recognition by the kappa- opioid receptor
J. Pept. Res., 65: 333-342 (2005)

Vig BS, Lorenzi PJ, Mittal S, Landowski CP, Shin HC, Mosberg HI, Hilfinger JM, Amidon GL
Amino acid ester prodrugs of floxuridine: synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis.
Pharm. Res., 20: 1381-1388 (2003)

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)

Mosberg HI, Fowler CB
Development and validation of opioid ligand-receptor interaction models: The structural basis of mu vs. delta selectivity
J. Peptide Res., 60: 329-332 (2002)

Hicks ME, Gomez-Flores R, Wang C, Mosberg HI, Weber RJ
Differential effects of the novel non-peptidic opioid 4-tyrosylamido-6-benzyl-1,2,3,4 tetrahydroquinoline (CGPM-9) on in vitro rat t lymphocyte and macrophage functions.
Life Sci., 68: 2685-2694 (2001)

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)

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)

Mosberg HI
Complementarity of delta opioid ligand pharmacophore and receptor models.
Biopolymers, 51: 426-39 (1999)

Butelman ER, Ko MC, Sobczyk-Kojiro K, Mosberg HI, Van Bemmel B, Zernig G, Woods JH
kappa-Opioid receptor binding populations in rhesus monkey brain: relationship to an assay of thermal antinociception.
J. Pharmacol. Exp. Ther., 285: 595-601 (1998)

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)

Mosberg HI, Ho JC, Sobczyk-Kojiro K
A high affinity, mu-opioid receptor-selective enkephalin analogue lacking an N-terminal tyrosine.
Bioorg. Med. Chem. Lett., 8: 2681-2684 (1998)

Lomize AL, Pogozheva ID, Mosberg HI
Development of a model for the delta-opioid receptor pharmacophore: 3. Comparison of the cyclic tetrapeptide, Tyr-c[D-Cys-Phe-D-Pen]OH with other conformationally constrained delta-receptor selective ligands.
Biopolymers., 38: 221-234 (1996)

Mosberg HI, Dua RK, Pogozheva ID, Lomize AL
Development of a model for the delta-opioid receptor pharmacophore. 4. Residue 3dehydrophenylalanine analogues of Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) confirmrequired gauche orientation of aromatic side chain.
Biopolymers, 39: 287-296 (1996)

Mosberg HI, Omnaas JR, Lomize AL, Heyl DL, Nordan I, Mousigian C, Davis P, Porreca F
Development of a model for the delta opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13).
J. Med. Chem., 37: 4384-4391 (1994)

Mosberg HI, Lomize AL, Wang C, Kroona H, Heyl DL, Sobczyk-Kojiro K, Ma W, Mousigian C, Porreca F
Development of a model for the delta opioid receptor pharmacophore. 1. Conformationally restricted Tyr1 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13).
J. Med. Chem., 37: 4371-4383 (1994)

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Design and synthesis of biologically active opioid peptides and peptidomimetics
Investigations of MOR and DOR trafficking and crosstalk
Development of mixed efficacy opioid ligands
Peptides and proteins in membranes
Homology modeling of GPCRs, important drug targets
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