Laura Bohn
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View article: Characterization of the GTPγS release function of a G protein-coupled receptor
Characterization of the GTPγS release function of a G protein-coupled receptor Open
G protein-coupled receptor (GPCR) signaling is one of the most ubiquitous and sensitive forms of cell surface reception. GPCRs stabilize the nucleotide-free state of heterotrimeric guanine-nucleotide binding proteins (G proteins); however,…
View article: GTP release-selective agonists prolong opioid analgesic efficacy
GTP release-selective agonists prolong opioid analgesic efficacy Open
G-protein-coupled receptors act as guanine nucleotide exchange factors (GEFs) and facilitate the activation of heterotrimeric G proteins by exchanging GDP for GTP1. This exchange function is not unidirectional2. Here we demonstrate that an…
View article: Bidirectional Modification of a <i>Galbulimima</i> Alkaloid Identifies Selective Opioid Ligands
Bidirectional Modification of a <i>Galbulimima</i> Alkaloid Identifies Selective Opioid Ligands Open
We report a bidirectional diversification and optimization campaign of the newly identified mu- and kappa-opioid receptor antagonist GB18, a naturally occurring Galbulimima alkaloid. First, we find that replacement of the GB18 piperidine w…
View article: Bidirectional modification of a Galbulimima alkaloid identifies selective opioid ligands
Bidirectional modification of a Galbulimima alkaloid identifies selective opioid ligands Open
We report a bidirectional diversification and optimization campaign of the newly identified mu- and kappa-opioid receptor antagonist GB18, a naturally occurring Galbulimima alkaloid. First, we find that replacement of the GB18 piperidine w…
View article: Triazole 187 is a biased KOR agonist that suppresses itch without sedation and induces anxiolytic-like behaviors in mice
Triazole 187 is a biased KOR agonist that suppresses itch without sedation and induces anxiolytic-like behaviors in mice Open
Kappa opioid receptor agonists are clinically used to treat pruritis and have therapeutic potential for the treatment of pain and neuropsychiatric disorders. We have previously shown that triazole 1.1 is a G protein signaling-biased KOR ag…
View article: Comparison of Agonist Activity between CB1 and CB2 Receptors with Orthosteric Site Mutations
Comparison of Agonist Activity between CB1 and CB2 Receptors with Orthosteric Site Mutations Open
Human endocannabinoid signaling is primarily mediated by the cannabinoid receptors, CB1 and CB2, which are G protein-coupled receptors (GPCRs). These receptors have been linked to a variety of physiological processes and are being pursued …
View article: Structural and functional insights into the G protein-coupled receptors: CB1 and CB2
Structural and functional insights into the G protein-coupled receptors: CB1 and CB2 Open
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 ma…
View article: A Route to Potent, Selective, and Biased Salvinorin Chemical Space
A Route to Potent, Selective, and Biased Salvinorin Chemical Space Open
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 a…
View article: Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine
Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine Open
Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum usi…
View article: Hyperactivity in mice induced by opioid agonists with partial intrinsic efficacy and biased agonism; alone and in combination with morphine
Hyperactivity in mice induced by opioid agonists with partial intrinsic efficacy and biased agonism; alone and in combination with morphine Open
Opioid analgesics like morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Here we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using 35 …
View article: A route to potent, selective and biased salvinorin chemical space
A route to potent, selective and biased salvinorin chemical space Open
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 am…
View article: Asymmetric Syntheses of (+)- and (−)-Collybolide Enable Reevaluation of <i>kappa</i> -Opioid Receptor Agonism
Asymmetric Syntheses of (+)- and (−)-Collybolide Enable Reevaluation of <i>kappa</i> -Opioid Receptor Agonism Open
The fungal metabolite collybolide has attracted attention as a non-nitrogenous, potent, and biased agonist of the kappa-opioid receptor (KOR). Here, we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile…
View article: Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism
Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism Open
The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile acces…
View article: Community guidelines for GPCR ligand bias: IUPHAR review 32
Community guidelines for GPCR ligand bias: IUPHAR review 32 Open
GPCRs modulate a plethora of physiological processes and mediate the effects of one‐third of FDA‐approved drugs. Depending on which ligand activates a receptor, it can engage different intracellular transducers. This ‘biased signalling’ pa…
View article: Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism
Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism Open
The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile acces…
View article: Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism
Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism Open
The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile acces…
View article: G protein signaling–biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists
G protein signaling–biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists Open
Significance Analgesic tolerance can result upon chronic use of opioid drugs necessitating dose escalation to treat pain. The biased mu opioid receptor agonist SR-17018 maintains antinociceptive efficacy without evidence of tolerance when …
View article: International Union of Basic and Clinical Pharmacology. Guidelines for GPCR ligand bias
International Union of Basic and Clinical Pharmacology. Guidelines for GPCR ligand bias Open
G protein-coupled receptors modulate a plethora of physiological processes and mediate the effects of one-third of FDA-approved drugs. Notably, depending on which ligand has activated a particular receptor, it can engage different intracel…
View article: Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists
Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists Open
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. Signaling 2020, 13, eaaz3140 10.1126/scisignal.aaz3140),…
View article: Enhanced Rewarding Properties of Morphine, but not Cocaine, in βarrestin-2 Knock-Out Mice
Enhanced Rewarding Properties of Morphine, but not Cocaine, in βarrestin-2 Knock-Out Mice Open
The reinforcing and psychomotor effects of morphine involve opiate stimulation of the dopaminergic system via activation of mu-opioid receptors (muOR). Both mu-opioid and dopamine receptors are members of the G-protein-coupled receptor (GP…
View article: Some effects of putative G-protein biased mu-opioid receptor agonists in male rhesus monkeys
Some effects of putative G-protein biased mu-opioid receptor agonists in male rhesus monkeys Open
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 …
View article: Novel Functionalized Cannabinoid Receptor Probes: Development of Exceptionally Potent Agonists
Novel Functionalized Cannabinoid Receptor Probes: Development of Exceptionally Potent Agonists Open
We report the development of novel cannabinergic probes that can stabilize the cannabinoid receptors (CBRs) through tight binding interactions. Ligand design involves the introduction of select groups at a judiciously chosen position withi…
View article: Low intrinsic efficacy alone cannot explain the improved side effect profiles of new opioid agonists
Low intrinsic efficacy alone cannot explain the improved side effect profiles of new opioid agonists Open
In a recent report in Science Signaling (DOI: 10.1126/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 v…
View article: Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain
Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain Open
The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies …
View article: Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria
Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria Open
Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria…