Arrestin-3 Agonism at Dopamine D3 Receptors Defines a Subclass of Second-Generation Antipsychotics That Promotes Drug Tolerance

Schamiloglu, Selin; Lewis, Elinor; Keeshen, Caroline M.; Hergarden, Anne C.; Bender, Kevin J.; Whistler, Jennifer L.

doi:10.1016/j.biopsych.2023.03.006

Cited by 7 publications

(2 citation statements)

References 82 publications

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“…This also means that it is theoretically possible for an agonist to be balanced at some doses and biased at others, or even G protein biased at some doses and arrestin biased at others ( Figure 6e ). This is not merely hypothetical, as some second-generation antipsychotics are arrestin biased, doing a better job of promoting endocytosis of their target receptors ( 32 ) and/or engaging arrestin-mediated signaling there ( 92 ).…”

Section: Barriers To Consensus: the Specifics And Semantics Of Pharma...mentioning

confidence: 99%

A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy

Gooding,

Whistler

2024

Annu. Rev. Physiol.

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The harmful side effects of opioid drugs such as respiratory depression, tolerance, dependence, and abuse potential have limited the therapeutic utility of opioids for their entire clinical history. However, no previous attempt to develop effective pain drugs that substantially ameliorate these effects has succeeded, and the current opioid epidemic affirms that they are a greater hindrance to the field of pain management than ever. Recent attempts at new opioid development have sought to reduce these side effects by minimizing engagement of the regulatory protein arrestin-3 at the mu-opioid receptor, but there is significant controversy around this approach. Here, we discuss the ongoing effort to develop safer opioids and its relevant historical context. We propose a new model that reconciles results previously assumed to be in direct conflict to explain how different signaling profiles at the mu-opioid receptor contribute to opioid tolerance and dependence. Our goal is for this framework to inform the search for a new generation of lower liability opioid analgesics. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Barriers To Consensus: the Specifics And Semantics Of Pharma...mentioning

confidence: 99%

A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy

Gooding,

Whistler

2024

Annu. Rev. Physiol.

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“…Although agonists with some selectivity exist, treatments are still suboptimal due to a lack of selectivity and different effects originating from the activation of both receptors 17,18 .…”

Section: Introductionmentioning

confidence: 99%

Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket

García-Nafría,

Arroyo-Urea,

Nazarova

et al. 2023

Preprint

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Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity, driven by the binding of the secondary pharmacophore to non-conserved regions of the receptor. Although bitopic ligands have great potential to improve current medications by reducing off-target side effects, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD3R coupled to a Go heterotrimer and bound to the D3R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide new insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.

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Uncovering Biased Signaling of Atypical Antipsychotics at Dopamine D3 Receptors in the Prefrontal Cortex

Avila-Zozaya

2023

Biological Psychiatry

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Arrestin-3 Agonism at Dopamine D3 Receptors Defines a Subclass of Second-Generation Antipsychotics That Promotes Drug Tolerance

Cited by 7 publications

References 82 publications

A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy

A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy

Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket

Uncovering Biased Signaling of Atypical Antipsychotics at Dopamine D3 Receptors in the Prefrontal Cortex

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