The current opioid prescription misuse epidemic has renewed interest in obtaining strong analgesic agents with decreased tolerance and addiction liability. Moreover, the high incidence of other side-effects with currently used opioid analgesics such as respiratory depression and constipation reduces their effectiveness in the pain clinic. Hence, there is a need either to develop new analgesics or to improve the clinical profile of existing medications. Morphine and related opioids exert their effects by acting at the orthosteric site on the mu-opioid receptor (MOR), i.e. the site where the endogenous opioid peptides bind. Recent advances in our knowledge of the structure of G-protein coupled receptors (GPCRs) has highlighted the possibility that GPCR function may be controlled by compounds binding at a separate, allosteric, site on the receptors. In this regard we have recently identified positive allosteric modulators (PAMs) that act at MOR (MOR-PAMs). These compounds increase the binding affinity of MOR agonists and the potency and/or maximal response to MOR agonists in vitro. Therefore, MOR-PAMs could possibly to be used as adjuncts to morphine and so reduce the level of opiate required to afford analgesia; thus producing the same functional analgesic response as a higher dose of morphine, but with reduced likelihood of the appearance of side-effects, including of tolerance and dependence. Perhaps more importantly, MOR-PAMs have the potential to be used alone to enhance the activity of endogenous opioid peptides. This would preserve the temporal and spatial characteristics of neuronal signaling and so avoid receptor down-regulation and other compensatory mechanisms that are induced by chronic MOR activation. In this application we seek to establish the value of allosteric modulation of MOR in vitro using an approach that involves investigation of the properties of allosteric modulation of MOR, structural biology to identify an allosteric binding site on MOR and development of improved allosteric probes. Detailed understanding of the actions of allosteric modulators of MOR will provide new information on mechanisms by which MOR function may be controlled and, together with the identification of high affinity probes, will pave the way for future drug development efforts of MOR modulators as analgesic adjunct drugs and/or novel analgesics.

Public Health Relevance

The proposed research is relevant to human health because it will increase our knowledge of the basic structure and working of the mu-opioid receptor and synthesize novel compounds for a newly identified binding site on this receptor. This could lead to the development of novel analgesics with reduced side-effects, especially tolerance and dependence. Our research is relevant to the mission of NIDA since it is designed to provide basic scientific knowledge and novel chemical entities/probes that could pave the way to improved management of pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
1R37DA039997-01
Application #
8945058
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Rapaka, Rao
Project Start
2015-07-01
Project End
2020-04-30
Budget Start
2015-07-01
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Livingston, Kathryn E; Traynor, John R (2018) Allostery at opioid receptors: modulation with small molecule ligands. Br J Pharmacol 175:2846-2856
Livingston, Kathryn E; Stanczyk, M Alexander; Burford, Neil T et al. (2018) Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors. Mol Pharmacol 93:157-167
Livingston, Kathryn E; Mahoney, Jacob P; Manglik, Aashish et al. (2018) Measuring ligand efficacy at the mu-opioid receptor using a conformational biosensor. Elife 7:
Healy, Jason R; Bezawada, Padmavani; Griggs, Nicholas W et al. (2017) Benzylideneoxymorphone: A new lead for development of bifunctional mu/delta opioid receptor ligands. Bioorg Med Chem Lett 27:666-669
Truong, Phong M; Hassan, Sergio A; Lee, Yong-Sok et al. (2017) Modulation of opioid receptor affinity and efficacy via N-substitution of 9?-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study. Bioorg Med Chem 25:2406-2422
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
Yao, Xin-Qiu; Malik, Rabia U; Griggs, Nicholas W et al. (2016) Dynamic Coupling and Allosteric Networks in the ? Subunit of Heterotrimeric G Proteins. J Biol Chem 291:4742-53