Regulator of G protein–signaling proteins and addictive drugs

Regulator of G protein–signaling (RGS) proteins are a family of more than 30 intracellular proteins that negatively modulate intracellular signaling of receptors in the G protein-coupled receptor family. This family includes receptors for opioids, cannabinoids, and dopamine that mediate the acute effects of addictive drugs or behaviors and chronic effects leading to the development of addictive disease. Members of the RGS protein family, by negatively modulating receptor signaling, influence the intracellular processes that lead to addiction. In turn, addictive drugs control the expression levels of several RGS proteins. This review will consider the distribution and mechanisms of action of RGS proteins, particularly the R4 and R7 families that have been implicated in the actions of addictive drugs, how knowledge of these proteins is contributing to an understanding of addictive processes, and whether specific RGS proteins could provide targets for the development of medications to manage and/or treat addiction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78669/1/j.1749-6632.2009.05150.x.pd

Measuring ligand efficacy at the mu-opioid receptor using a conformational biosensor.

The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (µ-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to µ-OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of µ-OR. We further show that positive allosteric modulators of µ-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell-free, signal transduction-independent and is generally applicable to GPCRs

Challenges for Opioid Receptor Nomenclature

Recent developments in the study of the structure and function of opioid receptors raise significant challenges for the definition of individual receptor types and the development of a nomenclature that precisely describes isoforms that may subserve different functions in vivo. Presentations at the 2013 meeting of the International Narcotics Research Conference in Cairns, Australia, considered some of the new discoveries that are now unravelling the complexities of opioid receptor signalling. Variable processing of opioid receptor messenger RNAs may lead to the presence of several isoforms of the μ receptor. Each opioid receptor type can function either as a monomer or as part of a homo- or heterodimer or higher multimer. Additionally, recent evidence points to the existence of agonist bias in the signal transduction pathways activated through μ receptors, and to the presence of regulatory allosteric sites on the receptors. This brief review summarizes the recent discoveries that raise challenges for receptor definition and the characterization of signal transduction pathways activated by specific receptor forms. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.NHMRC 104596

The δ‐opioid receptor positive allosteric modulator BMS 986187 is a G‐protein‐biased allosteric agonist

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149355/1/bph14602.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149355/2/bph14602_am.pd

Translation of structure‐activity relationships from cyclic mixed efficacy opioid peptides to linear analogues

Most opioid analgesics used in the treatment of pain are mu opioid receptor (MOR) agonists. While effective, there are significant drawbacks to opioid use, including the development of tolerance and dependence. However, the coadministration of a MOR agonist with a delta opioid receptor (DOR) antagonist slows the development of MOR‐related side effects, while maintaining analgesia. We have previously reported a series of cyclic mixed efficacy MOR agonist/DOR antagonist ligands. Here we describe the transfer of key features from these cyclic analogs to linear sequences. Using the linear MOR/DOR agonist, Tyr‐DThr‐Gly‐Phe‐Leu‐Ser‐NH 2 ( DTLES ), as a lead scaffold, we replaced Phe 4 with bulkier and/or constrained aromatic residues shown to confer DOR antagonism in our cyclic ligands. These replacements failed to confer DOR antagonism in the DTLES analogs, presumably because the more flexible linear ligands can adopt binding poses that will fit in the narrow binding pocket of the active conformations of both MOR and DOR. Nonetheless, the pharmacological profile observed in this series, high affinity and efficacy for MOR and DOR with selectivity relative to KOR, has also been shown to reduce the development of unwanted side effects. We further modified our lead MOR/DOR agonist with a C‐terminal glucoserine to improve bioavailability. The resulting ligand displayed high efficacy and potency at both MOR and DOR and no efficacy at KOR. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 107–114, 2014.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102641/1/bip22437.pd

Benzylideneoxymorphone: A New Lead for Development of Bifunctional Mu/Delta Opioid Receptor Ligands

Opioid analgesic tolerance remains a considerable drawback to chronic pain management. The finding that concomitant administration of delta opioid receptor (DOR) antagonists attenuates the development of tolerance to mu opioid receptor (MOR) agonists has led to interest in producing bifunctional MOR agonist/DOR antagonist ligands. Herein, we present 7-benzylideneoxymorphone (6, UMB 246) displaying MOR partial agonist/DOR antagonist activity, representing a new lead for designing bifunctional MOR/DOR ligands

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Turf and Lawn Grass Association Better turf through research and Educatio

Design of high affinity cyclic pentapeptide ligands for Κ-opioid receptors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73319/1/j.1399-3011.2005.00295.x.pd

Roles of residues 3 and 4 in cyclic tetrapeptide ligand recognition by the Κ -opioid receptor

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75723/1/j.1399-3011.2005.00220.x.pd