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Article ; Online: Structural and functional insights into the G protein-coupled receptors: CB1 and CB2.

Brust, Christina A / Swanson, Matthew A / Bohn, Laura M

2023 Volume 51, Issue 4, Page(s) 1533–1543

Abstract: The cannabinoid receptors CB1 and CB2 mediate a variety of physiological processes and continue to be explored as desirable drug targets. Both receptors are activated by the endogenous endocannabinoids and the psychoactive components of marijuana. Over ... ...

Abstract	The cannabinoid receptors CB1 and CB2 mediate a variety of physiological processes and continue to be explored as desirable drug targets. Both receptors are activated by the endogenous endocannabinoids and the psychoactive components of marijuana. Over the years, many efforts have been made to make selective ligands; however, the high degree of homology between cannabinoid receptor subtypes introduces challenges in studying either receptor in isolation. Recent advancements in structure biology have resulted in a surge of high-resolution structures, enriching our knowledge and understanding of receptor structure and function. In this review, of recent cannabinoid receptor structures, key features of the inactive and active state CB1 and CB2 are presented. These structures will provide additional insight into the modulation and signaling mechanism of cannabinoid receptors CB1 and CB2 and aid in the development of future therapeutics.
MeSH term(s)	Receptors, G-Protein-Coupled ; Signal Transduction ; Drug Delivery Systems ; Endocannabinoids ; Receptors, Cannabinoid
Chemical Substances	Receptors, G-Protein-Coupled ; Endocannabinoids ; Receptors, Cannabinoid
Language	English
Publishing date	2023-08-18
Publishing country	England
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20221316
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Zs.A 944: Show issues

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Article ; Online: Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists.

Stahl, Edward L / Bohn, Laura M

Biochemistry

2021 Volume 61, Issue 18, Page(s) 1923–1935

Abstract: In a recent report ... ...

Abstract	In a recent report in
MeSH term(s)	Analgesics, Opioid/adverse effects ; Animals ; Benzimidazoles ; GTP-Binding Proteins/metabolism ; Mice ; Piperidines ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Opioid, mu/agonists ; Signal Transduction
Chemical Substances	Analgesics, Opioid ; Benzimidazoles ; Piperidines ; Receptors, G-Protein-Coupled ; Receptors, Opioid, mu ; sr-17018 ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2021-09-01
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.1c00466
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Zs.A 217: Show issues

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Article ; Online: Decaf or regular? Energizing the caffeine receptor.

Stahl, Edward L / Bohn, Laura M

Cell

2021 Volume 184, Issue 7, Page(s) 1659–1660

Abstract: Partial agonism describes the relative efficacy of a drug compared to one that produces a greater response in a particular system; the designation is dependent upon the comparator and the system. In this issue of Cell, Huang et al. describe biophysical ... ...

Abstract	Partial agonism describes the relative efficacy of a drug compared to one that produces a greater response in a particular system; the designation is dependent upon the comparator and the system. In this issue of Cell, Huang et al. describe biophysical approaches to define the signature of GPCR partial agonists, providing direct measures of varying intrinsic efficacy.
MeSH term(s)	Caffeine
Chemical Substances	Caffeine (3G6A5W338E)
Language	English
Publishing date	2021-04-02
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2021.03.016
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists

Stahl, Edward L. / Bohn, Laura M.

Biochemistry. 2021 Sept. 01, v. 61, no. 18

2021

Abstract: In a recent report in Science Signaling (Gillis, A., et al. Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci. Signaling2020, 13, eaaz314010.1126/scisignal.aaz3140), it was suggested ...

Abstract	In a recent report in Science Signaling (Gillis, A., et al. Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci. Signaling2020, 13, eaaz314010.1126/scisignal.aaz3140), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. Although many of the compounds that were tested have been shown to display G protein signaling bias in prior publications, the authors conclude that because they cannot detect biased agonism in their cellular signaling studies the compounds are therefore not biased agonists. Rather, they conclude that it is low intrinsic efficacy that leads to the therapeutic window improvement. Intrinsic efficacy is the extent to which an agonist can stimulate a G protein-coupled receptor response in a system, while biased agonism takes into consideration not only the intrinsic efficacy but also the potency of an agonist in an assay. Herein, we have reanalyzed the data presented in the published work (10.1126/scisignal.aaz3140) [including the recent Erratum (10.1126/scisignal.abf9803)] to derive intrinsic efficacy and bias factors as ΔΔlog(τ/KA) and ΔΔlog(Emax/EC₅₀), respectively. On the basis of this reanalysis, the data support the conclusion that biased agonism, favoring G protein signaling, was observed. Moreover, a conservation of rank order intrinsic efficacy was not observed upon comparing responses in each assay, further suggesting that multiple active receptor states were present. These observations agree with prior studies in which oliceridine, PZM21, and SR-17018 were first described as biased agonists with improvement in antinociception over respiratory suppression in mice. Therefore, the data in the Science Signaling paper provide strong corroborating evidence that G protein signaling bias may be a means of improving opioid analgesia while avoiding certain undesirable side effects.
Keywords	G-protein coupled receptors ; adverse effects ; agonists ; analgesia ; paper
Language	English
Dates of publication	2021-0901
Size	p. 1923-1935.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.1c00466
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 217: Show issues

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Article: A Route to Potent, Selective, and Biased Salvinorin Chemical Space.

Hill, Sarah J / Dao, Nathan / Dang, Vuong Q / Stahl, Edward L / Bohn, Laura M / Shenvi, Ryan A

ACS central science

2023 Volume 9, Issue 8, Page(s) 1567–1574

Abstract: The salvinorins serve as templates for next generation analgesics, antipruritics, and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind ... ...

Abstract	The salvinorins serve as templates for next generation analgesics, antipruritics, and dissociative hallucinogens via selective and potent agonism of the kappa-opioid receptor (KOR). In contrast to most opioids, the salvinorins lack basic amines and bind with high affinity and selectivity via complex polyoxygenated scaffolds that have frustrated deep-seated modification by synthesis. Here we describe a short asymmetric synthesis that relies on a sterically confined organocatalyst to dissociate acidity from reactivity and effect Robinson annulation of an unactivated nucleophile/unstable electrophile pair. Combined with a cobalt-catalyzed polarized diene-alkyne cycloaddition, the route allows divergent access to a focused library of salvinorins. We appraise the synthesis by its generation of multiple analogs that exceed the potency, selectivity, stability, and functional bias of salvinorin A itself.
Language	English
Publishing date	2023-07-12
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.3c00616
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Article: Seeking (and Finding) Biased Ligands of the Kappa Opioid Receptor.

Bohn, Laura M / Aubé, Jeffrey

ACS medicinal chemistry letters

2017 Volume 8, Issue 7, Page(s) 694–700

Abstract: The discovery and characterization of two classes of kappa opioid receptor agonists that are biased for G protein over βarrestin signaling are described. ...

Abstract	The discovery and characterization of two classes of kappa opioid receptor agonists that are biased for G protein over βarrestin signaling are described.
Language	English
Publishing date	2017-07-05
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.7b00224
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Article ; Online: Quantitating Ligand Bias Using the Competitive Model of Ligand Activity.

Stahl, Edward L / Ehlert, Frederick J / Bohn, Laura M

Methods in molecular biology (Clifton, N.J.)

2019 Volume 1957, Page(s) 235–247

Abstract: G protein-coupled receptors (GPCRs) can interact with both G proteins and β-arrestin proteins to propagate different signaling outputs. In some contexts, agonists may drive the receptor to preferentially engage one of these effectors over the other. Such ...

Abstract	G protein-coupled receptors (GPCRs) can interact with both G proteins and β-arrestin proteins to propagate different signaling outputs. In some contexts, agonists may drive the receptor to preferentially engage one of these effectors over the other. Such "ligand bias" may present a means to impart pathway-selective signaling downstream of this class of receptors. In cases where physiological responses are mediated by diverse pathways, this could, in part, provide a means to refine GPCR therapeutics. Cell-based signaling assays are used to measure the potential for signaling bias in vitro, and these measures take into account potency, efficacy, and the overall capacity of the assay. However, narrow assay windows sometimes limit the confidence in estimating agonist activity, if a compound performs as a very weakly efficacious partial agonist. This lack of response in an assay hampers the ability to measure and compare potencies, and the degree of separation of an agonist's performance, between two assays. In this chapter, we describe in detail a method for the estimation of the relative activity of a partial agonist and provide a stepwise protocol for calculating bias when this case arises.
MeSH term(s)	Bias ; Biological Assay/methods ; Confidence Intervals ; Ligands ; Models, Biological ; Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Ligands ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2019-03-27
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9158-7_15
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Toward Directing Opioid Receptor Signaling to Refine Opioid Therapeutics.

Grim, Travis W / Acevedo-Canabal, Agnes / Bohn, Laura M

Biological psychiatry

2019 Volume 87, Issue 1, Page(s) 15–21

Abstract: The mu opioid receptor (MOR) is a diversely regulated target for the alleviation of pain in the clinical setting. However, untoward side effects such as tolerance, dependence, respiratory suppression, constipation, and abuse liability detract from the ... ...

Abstract	The mu opioid receptor (MOR) is a diversely regulated target for the alleviation of pain in the clinical setting. However, untoward side effects such as tolerance, dependence, respiratory suppression, constipation, and abuse liability detract from the general activation of these receptors. Studies in genetically modified rodent models suggest that activating G protein signaling pathways while avoiding phosphorylation of the receptor or recruitment of β-arrestin scaffolding proteins could preserve the analgesic properties of MOR agonists while avoiding certain side effects. With the development of novel MOR "biased" agonists, which lead to preferential activation of G protein pathways over receptor phosphorylation, internalization, or interaction with other effectors, this hypothesis can be tested in a native, physiological setting. Overall, it is clear that the MOR is not a simple on-off switch and that the diverse means by which the receptor can be regulated may present an opportunity to refine therapeutics for the treatment of pain.
MeSH term(s)	Analgesics, Opioid/pharmacology ; beta-Arrestins/metabolism ; Pain/drug therapy ; Receptors, Opioid, mu/metabolism ; Signal Transduction ; Humans
Chemical Substances	Analgesics, Opioid ; beta-Arrestins ; Receptors, Opioid, mu
Language	English
Publishing date	2019-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2019.10.020
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Zs.A 720: Show issues

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Article ; Online: Some effects of putative G-protein biased mu-opioid receptor agonists in male rhesus monkeys.

Cornelissen, Jeremy C / Blough, Bruce E / Bohn, Laura M / Negus, S Stevens / Banks, Matthew L

Behavioural pharmacology

2021 Volume 32, Issue 5, Page(s) 453–458

Abstract: G-protein-biased mu-opioid receptor (GPB-MOR) agonists are an emerging class of compounds being evaluated as candidate analgesics and agonist medications for opioid use disorder. Most of the basic pharmacology of GPB-MOR agonists has been conducted in ... ...

Abstract	G-protein-biased mu-opioid receptor (GPB-MOR) agonists are an emerging class of compounds being evaluated as candidate analgesics and agonist medications for opioid use disorder. Most of the basic pharmacology of GPB-MOR agonists has been conducted in rodents and much less is known how the basic behavioral pharmacology of these compounds translates to nonhuman primates. The present study determined the antinociceptive potency and time course of three putative GPB-MOR agonists: (+)-oliceridine (i.e. TRV130), SR14968, and SR17018 in male rhesus monkeys (n = 3). In addition, the respiratory effects of these compounds were also indirectly determined using a pulse oximeter to measure percent peripheral oxygen saturation (%SpO2). The largest intramuscular oliceridine dose (3.2 mg/kg) produced significant antinociception at 50°C, but not 54°C, and peak effects were between 10 and 30 min. Oliceridine also decreased SpO2 below the 90% threshold that would be clinically categorized as hypoxia in two out of three monkeys. The largest intramuscular SR14968 dose (0.32 mg/kg) produced 100% MPE at 50°C, but not 54°C, in two out of three monkeys, and peak effects were between 30 and 100 min. The largest intravenous SR17018 dose (1 mg/kg) produced 100% MPE at 50°C, but not 54°C, in the same two out of three monkeys, and peak effects were between 30 and 100 min. Solubility limitations for both SR14968 and SR17018 impaired our ability to determine in-vivo potency and effectiveness on antinociceptive and %SpO2 measures for these two compounds.
MeSH term(s)	Analgesics/pharmacology ; Animals ; Behavior, Animal ; Drug Evaluation/methods ; GTP-Binding Proteins/metabolism ; Macaca mulatta ; Male ; Opioid-Related Disorders/drug therapy ; Oximetry/methods ; Pain/drug therapy ; Receptors, Opioid, mu/agonists ; Receptors, Opioid, mu/metabolism ; Respiration/drug effects ; Spiro Compounds/pharmacology ; Thiophenes/pharmacology
Chemical Substances	((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine ; Analgesics ; Receptors, Opioid, mu ; Spiro Compounds ; Thiophenes ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2021-03-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1027374-8
ISSN	1473-5849 ; 0955-8810
ISSN (online)	1473-5849
ISSN	0955-8810
DOI	10.1097/FBP.0000000000000634
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Zs.A 2883: Show issues

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Article ; Online: Advances in Sulfonamide Kappa Opioid Receptor Antagonists: Structural Refinement and Evaluation of CNS Clearance.

Ma, Huiyong / Brust, Tarsis / Frankowski, Kevin J / Lovell, Kimberly M / Cameron, Michael D / Bohn, Laura M / Aubé, Jeffrey

ACS chemical neuroscience

2022 Volume 13, Issue 8, Page(s) 1315–1332

Abstract: Focused modification of a sulfonamide-based kappa opioid receptor (KOR) antagonist series previously reported by this laboratory was investigated. A total of 32 analogues were prepared to explore linker replacement, constraint manipulation, and aryl ... ...

Abstract	Focused modification of a sulfonamide-based kappa opioid receptor (KOR) antagonist series previously reported by this laboratory was investigated. A total of 32 analogues were prepared to explore linker replacement, constraint manipulation, and aryl group or amine substitution. All analogues were assayed for KOR antagonist activity, and the initial lead compound was assessed for
MeSH term(s)	Narcotic Antagonists/chemistry ; Narcotic Antagonists/pharmacology ; Receptors, Opioid, kappa ; Sulfonamides/pharmacology ; Tetrahydroisoquinolines/chemistry
Chemical Substances	Narcotic Antagonists ; Receptors, Opioid, kappa ; Sulfonamides ; Tetrahydroisoquinolines
Language	English
Publishing date	2022-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Research Support, N.I.H., Extramural
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00140
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