The Buprenorphine Analogue BU10119 Attenuates Drug-Primed and Stress-Induced Cocaine Reinstatement in Mice

Hillhouse, Todd M.; Olson, Karin; Hallahan, James E.; Rysztak, Lauren G.; Sears, Bryan; Meurice, Claire; Ostovar, Mehrnoosh; Koppenhaver, Peyton O.; West, Joshua L.; Jutkiewicz, Emily M.; Husbands, Stephen M.; Traynor, John R.

doi:10.1124/jpet.121.000524

Cited by 11 publications

(12 citation statements)

References 59 publications

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“…However, the application and further development of peptide formulations provide promise on this front. Moreover, combining the benefits of AMs with advantages from other drug design principles, such as targeting multiple receptors to reduce side effects and improve effectiveness, is a promising future direction for the field (Giri et al, 2015;Olson et al, 2017;Olson et al, 2019;Hillhouse and et al, 2021). Lastly, peptide and peptidomimetic AMs designed from protein-protein interactions that harness structure-based drug design principles are promising future avenues with the increasing availability of GPCR:protein structures.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators

2021

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Allosteric modulators (AMs) of G-protein coupled receptors (GPCRs) are desirable drug targets because they can produce fewer on-target side effects, improved selectivity, and better biological specificity (e.g., biased signaling or probe dependence) than orthosteric drugs. An underappreciated source for identifying AM leads are peptides and proteins—many of which were evolutionarily selected as AMs—derived from endogenous protein-protein interactions (e.g., transducer/accessory proteins), intramolecular receptor contacts (e.g., pepducins or extracellular domains), endogenous peptides, and exogenous libraries (e.g., nanobodies or conotoxins). Peptides offer distinct advantages over small molecules, including high affinity, good tolerability, and good bioactivity, and specific disadvantages, including relatively poor metabolic stability and bioavailability. Peptidomimetics are molecules that combine the advantages of both peptides and small molecules by mimicking the peptide’s chemical features responsible for bioactivity while improving its druggability. This review 1) discusses sources and strategies to identify peptide/peptidomimetic AMs, 2) overviews strategies to convert a peptide lead into more drug-like “peptidomimetic,” and 3) critically analyzes the advantages, disadvantages, and future directions of peptidomimetic AMs. While small molecules will and should play a vital role in AM drug discovery, peptidomimetics can complement and even exceed the advantages of small molecules, depending on the target, site, lead, and associated factors.

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Section: Discussionmentioning

confidence: 99%

Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators

2021

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“…Mice ( N = 12; six male, six female) were each placed into a 5,000 mL glass cylinder (Pyrex graduated beaker) filled with 3,000 mL of 25 °C ± 1 °C water for 10 min (Hillhouse et al, 2021). The 10-min swim stress was not video recorded.…”

Section: Methodsmentioning

confidence: 99%

Differential effects of repeated fluoxetine and ketamine administration on behavioral and pharmacological stressor-induced depression of digging behavior in mice.

Partridge,

Hillhouse

2024

Experimental and Clinical Psychopharmacology

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Major depressive disorder is a multifactorial disorder that originates from a complex web of variables and overlaps with similar disorders (e.g., depression and anxiety). As such, animal models should account for the considerable symptom overlap between psychiatric disorders. We sought to extend the findings of behavioral assays that encompass both anxiety and stress/depression components. To do so, we have focused on digging behavior, a compulsive-like behavior displayed in mice, in which we employed behavioral and pharmacological stressors to reduce digging behaviors, producing a depression-like state. Locomotor activity was assessed during each test session. We found that digging behavior remains consistent, but locomotor activity decreased when exposed to multiple test sessions over 4 weeks and no sex differences were observed. A time-course study showed a single swim stress significantly reduced digging behavior for at least 3 days but rebounded to baseline levels by Day 7. Repeated treatment of 10 mg/kg/day fluoxetine, but not ketamine, partially reversed swim stress-induced depression of digging behavior on Days 3 and 7. The pharmacological stressor yohimbine (1.0-5.0 mg/kg) dose-dependently decreased digging behavior. Repeated treatment of 10 mg/kg/day ketamine, but not fluoxetine, reversed yohimbineinduced depression of digging behavior on Days 3 and 7. These data suggest that digging behavior is a stable and consistent behavior displayed by all mice. We were able to depress digging behavior with both behavioral and pharmacological stress. However, the reversal of stress-induced depression of digging behavior was stimulus-(e.g., behavioral vs. pharmacological) and drug-dependent and will require further investigation. Public Health SignificanceResearchers have argued that psychiatric disorders should be viewed on a spectrum to account for overlap between disorders. As such, animal models should account for the considerable symptom overlap between psychiatric disorders. This study indicates that behavioral and pharmacological stressors can be added to the assay of compulsive digging to depress digging behavior in mice (moving toward an animal model with an anxiety/compulsive and depression component), which can be reversed by clinically approved antidepressant drugs.

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“…Moreover, there remains a need for transient transfection before each experimental run and further miniaturize conditions to 384-well and 1536-well plates for BRET and, to a lesser extent, FRET. Finally, other desirable drug profiles, such as allosteric modulators, ligand binding to GPCR heteromers, and multifunctional ligands that bind to multiple homomeric receptors (e.g., refs and − ), could be further explored and evaluated using future iterations of conformational biosensors. The continued optimization of conformational biosensors will assuredly address these issues.…”

Section: Conformational Biosensor Platforms For High Throughput Scree...mentioning

confidence: 99%

Finding the Perfect Fit: Conformational Biosensors to Determine the Efficacy of GPCR Ligands

Olson

Campbell

Alt

et al. 2022

ACS Pharmacol. Transl. Sci.

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G protein-coupled receptors (GPCRs) are highly druggable targets that adopt numerous conformations. A ligand’s ability to stabilize specific conformation(s) of its cognate receptor determines its efficacy or ability to produce a biological response. Identifying ligands that produce different receptor conformations and potentially discrete pharmacological effects (e.g., biased agonists, partial agonists, antagonists, allosteric modulators) is a major goal in drug discovery and necessary to develop drugs with better effectiveness and fewer side effects. Fortunately, direct measurements of ligand efficacy, via receptor conformational changes are possible with the recent development of conformational biosensors. In this review, we discuss classical efficacy models, including the two-state model, the ternary-complex model, and multistate models. We describe how nanobody-, transducer-, and receptor-based conformational biosensors detect and/or stabilize specific GPCR conformations to identify ligands with different levels of efficacy. In particular, conformational biosensors provide the potential to identify and/or characterize therapeutically desirable but often difficult to measure conformations of receptors faster and better than current methods. For drug discovery/development, several recent proof-of-principle studies have optimized conformational biosensors for high-throughput screening (HTS) platforms. However, their widespread use is limited by the fact that few sensors are reliably capable of detecting low-frequency conformations and technically demanding assay conditions. Nonetheless, conformational biosensors do help identify desirable ligands such as allosteric modulators, biased ligands, or partial agonists in a single assay, representing a distinct advantage over classical methods.

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The Buprenorphine Analogue BU10119 Attenuates Drug-Primed and Stress-Induced Cocaine Reinstatement in Mice

Cited by 11 publications

References 59 publications

Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators

Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators

Differential effects of repeated fluoxetine and ketamine administration on behavioral and pharmacological stressor-induced depression of digging behavior in mice.

Finding the Perfect Fit: Conformational Biosensors to Determine the Efficacy of GPCR Ligands

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