The potential benefit of simultaneously attacking multiple targets in order to improve therapeutic outcomes has become increasingly clear. This is illustrated in the field of opioid analgesics, where the co- administration of a mu opioid receptor (MOR) agonist with a delta opioid receptor (DOR) antagonist retains the MOR-mediated analgesia but with reduced negative side effects, such as the development of tolerance and dependence, features that limit the clinical use of opioid analgesics. Clinically, it would be preferred to administer a single bifunctional drug containing both opioid receptor actions: MOR agonism to promote analgesia along with DOR antagonism to prevent MOR tolerance and dependence development during chronic administration. We propose to develop such compounds by extending our very promising initial studies that have led to both peptide and non-peptide ligands displaying the desired MOR agonist/DOR antagonist profile and which are active after intraperitoneal administration. We will simultaneously elaborate and improve both peptide and non-peptide series. For the peptide series, our focus will be on increasing potency and MOR efficacy and on improving bioavailability, the latter primarily through glycosylation. For the non-peptide compounds, we will pursue three related peptidomimetic series with the major aims of equalizing MOR and DOR affinity and increasing metabolic stability. A panel of pharmacological and pharmacokinetic assays will be used to evaluate new compounds and to select those best suited for more extensive in vivo analysis. As always, our design of new compounds will be driven by our ligand-receptor structural models which we have successfully demonstrated to be highly valuable for structure-based design.

Public Health Relevance

Opioid drugs such as morphine are the primary treatment for severe pain, however development of tolerance to and dependence on these drugs limits their usefulness. Evidence exists that the desired actions of opioids can be separated from the undesired side effects by simultaneously targeting two different types of opioid receptors. Our goal is to develop single, bifunctional agents that achieve this and thus have potential as safer opioid analgesics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA003910-27
Application #
8503677
Study Section
Special Emphasis Panel (DDNS)
Program Officer
Hillery, Paul
Project Start
1985-08-01
Project End
2018-01-31
Budget Start
2013-05-15
Budget End
2014-01-31
Support Year
27
Fiscal Year
2013
Total Cost
$516,831
Indirect Cost
$180,984
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Anand, Jessica P; Porter-Barrus, Vanessa R; Waldschmidt, Helen V et al. (2014) Translation of structure-activity relationships from cyclic mixed efficacy opioid peptides to linear analogues. Biopolymers 102:107-14
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
Kumar, Vinod; Ridzwan, Irna E; Grivas, Konstantinos et al. (2014) Selectively promiscuous opioid ligands: discovery of high affinity/low efficacy opioid ligands with substantial nociceptin opioid peptide receptor affinity. J Med Chem 57:4049-57
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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