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 #
4R01DA003910-30
Application #
9012027
Study Section
Special Emphasis Panel (DDNS)
Program Officer
Hillery, Paul
Project Start
1985-08-01
Project End
2018-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
30
Fiscal Year
2016
Total Cost
$511,662
Indirect Cost
$179,174
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; Kochan, Kelsey E; Nastase, Anthony F et al. (2018) In vivo effects of ?-opioid receptor agonist/?-opioid receptor antagonist peptidomimetics following acute and repeated administration. Br J Pharmacol 175:2013-2027
Anand, Jessica P; Boyer, Brett T; Mosberg, Henry I et al. (2016) The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice. Psychopharmacology (Berl) 233:2479-87
Harland, Aubrie A; Bender, Aaron M; Griggs, Nicholas W et al. (2016) Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy ?-Opioid Receptor (MOR)/?-Opioid Receptor (DOR) Ligands. J Med Chem 59:4985-98
Bender, Aaron M; Griggs, Nicholas W; Anand, Jessica P et al. (2015) Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy ? opioid receptor/? opioid receptor ligands. ACS Chem Neurosci 6:1428-35
Geng, Jie; Pogozheva, Irina D; Mosberg, Henry I et al. (2015) Use of Functional Polymorphisms To Elucidate the Peptide Binding Site of TAP Complexes. J Immunol 195:3436-48
Harland, Aubrie A; Yeomans, Larisa; Griggs, Nicholas W et al. (2015) Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy ?-Opioid Receptor (MOR) Agonists/?-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities. J Med Chem 58:8952-69
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
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
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

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