The rational design of opioid drugs requires a detailed understanding of the precise interactions between opioid ligand and opioid receptor that underlie ligand selectivity for a particular opioid receptor and that distinguish agonist from antagonist function. During the current grant period our efforts to gain that understanding have focused on the refinement and validation of models of ligand/receptor complexes for the mu and delta opioid receptors (MOR and DOR) and elucidation of the precise features of ligand-receptor interaction that differentiate binding to MOR and DOR. In the next grant period, we propose to extend these studies by applying the insights gained from initial cyclic KOR (kappa opioid receptor) peptide ligands that display high affinity but are nonselective, and from our ligand-receptor interaction models for MOR, DOR, and KOR to design new KOR ligands within the same series that achieve KOR selectivity through KOR-specific receptor interactions. We will also begin a similar process of structure based ligand design for the orphan receptor, ORL1, using a cyclic pentapeptide scaffold. If successful, these studies would represent the considerable achievement of structure-based design of structurally related selective ligands for all 4 classes of opioid receptors, two of which (KOR and ORL1) typically bind only larger peptide ligands. Further, we will follow-up exciting initial results that point to features that determine efficacy. Success in these studies would be a clear indicator of the accuracy of the ligand/receptor interaction models and the applicability of our approaches to a wide array of GPCRs. Finally, we will continue our efforts aimed at transferring peptide-derived pharmacophore information to peptidomimetic scaffolds that hold much greater potential as possible CNS active clinical agents.
The interaction of opioid drugs with their protein targets initiates the desirable and undesirable effects of these drugs. Gaining a precise understanding of these interactions is the first step toward the design and development of opioid drugs with more tailored actions, especially opioids with reduced tolerance, dependence liability, and abuse potential.
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|Mosberg, Henry I; Yeomans, Larisa; Anand, Jessica P et al. (2014) Development of a bioavailable ? opioid receptor (MOPr) agonist, ? opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance. J Med Chem 57:3148-53|
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|Pogozheva, Irina D; Mosberg, Henry I; Lomize, Andrei L (2014) Life at the border: adaptation of proteins to anisotropic membrane environment. Protein Sci 23:1165-96|
|Bender, Aaron M; Clark, Mary J; Agius, Michael P et al. (2014) Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity ? opioid receptor (MOR) agonist/? opioid receptor (DOR) antagonist ligands. Bioorg Med Chem Lett 24:548-51|
|Pogozheva, Irina D; Tristram-Nagle, Stephanie; Mosberg, Henry I et al. (2013) Structural adaptations of proteins to different biological membranes. Biochim Biophys Acta 1828:2592-608|
|Mosberg, Henry I; Yeomans, Larisa; Harland, Aubrie A et al. (2013) Opioid peptidomimetics: leads for the design of bioavailable mixed efficacy ýý opioid receptor (MOR) agonist/ýý opioid receptor (DOR) antagonist ligands. J Med Chem 56:2139-49|
|Lomize, Mikhail A; Pogozheva, Irina D; Joo, Hyeon et al. (2012) OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res 40:D370-6|
|Lomize, Andrei L; Pogozheva, Irina D; Mosberg, Henry I (2011) Anisotropic solvent model of the lipid bilayer. 1. Parameterization of long-range electrostatics and first solvation shell effects. J Chem Inf Model 51:918-29|
|Lomize, Andrei L; Pogozheva, Irina D; Mosberg, Henry I (2011) Anisotropic solvent model of the lipid bilayer. 2. Energetics of insertion of small molecules, peptides, and proteins in membranes. J Chem Inf Model 51:930-46|
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