Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket DOI Creative Commons
Javier García‐Nafría, Sandra Arroyo‐Urea,

Antonina Nazarova

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 19, 2023

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

Language: Английский

Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites DOI Creative Commons
Andrew D. Nelson, Amanda M. Catalfio,

Julie P. Gupta

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(7), P. 1133 - 1149.e6

Published: Jan. 29, 2024

Language: Английский

Citations

19
Progress on the development of Class A GPCR‐biased ligands DOI Creative Commons
Paula Morales, Magdalena M. Scharf, Marcel Bermúdez

et al.

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 11, 2024

Class A G protein‐coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and importance as drug targets. Although numerous drugs the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, adverse effects triggered by available unbiased GPCR modulators, limit use therapeutic value. In this context, elucidation of biased has opened up new pharmacological avenues holding promise safer therapeutics. Functionally selective ligands favour receptor conformations facilitating recruitment specific effectors modulation associated pathways. This review surveys current discovery landscape GPCR‐biased modulators with a focus on recent advances. Understanding biological preferential coupling is at different stages depending family. Therefore, individual families, we present compilation functionally reported past few years. doing so, dissect relevance, molecular determinants potential clinical applications.

Language: Английский

Citations

6
A nanoluciferase complementation-based assay for monitoring β-arrestin2 recruitment to the dopamine D3 receptor DOI Creative Commons

Viktor Burström,

Kuiying Xu,

Emilio Garro-Martínez

et al.

Biochemistry and Biophysics Reports, Journal Year: 2025, Volume and Issue: 42, P. 102019 - 102019

Published: April 18, 2025

Language: Английский

Citations

0
D3 dopamine receptors implicate a subtype of medium spiny neuron in the aversive effects of antipsychotic medications DOI Creative Commons

Elinor Lewis,

Jessie Muir,

Ying C. Li

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 20, 2025

Abstract Second generation antipsychotics (SGAs) are widely used clinical tools, yet they often cause negative side effects and take weeks to become effective, leading poor patient compliance. The effect/side effect profile of individual SGAs is highly variable, the mechanisms that underlie this variability not well understood. We found SGA activity at D3 dopamine receptors (D3R) in Nucleus Accumbens (NAc) mediates aversive SGAs. Using single-nucleus RNA sequencing, we D3R expressed a subpopulation D1R neurons defines its own distinct NAc cell type. demonstrate while multiple (clozapine quetiapine) acute conditioned place aversion mice, only chronic treatment with quetiapine, an arrestin-biased agonist D3R, causes abate. further show both population level quetiapine inhibits D3R-neurons lateral shell (LatSh) NAc. Selective optogenetic inhibition LatSh produces real time implicating type Our findings suggest cellular systems-level mechanism underlying highlight pathway selective tolerance aversion, providing framework for future therapeutic strategies development.

Language: Английский

Citations

0
A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy DOI Creative Commons
Sarah Gooding, Jennifer L. Whistler

Annual Review of Physiology, Journal Year: 2023, Volume and Issue: 86(1), P. 1 - 25

Published: Nov. 29, 2023

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

Language: Английский

Citations

6
Low-dose lithium mono- and adjunctive therapies improve MK-801-induced cognitive impairment and schizophrenia-like behavior in mice - Evidence from altered prefrontal lobe Ca2+ activity DOI
Chuanjun Zhuo, Hongjun Tian, Guangdong Chen

et al.

Journal of Affective Disorders, Journal Year: 2023, Volume and Issue: 337, P. 128 - 142

Published: May 25, 2023

Language: Английский

Citations

5
A Review on Indole-triazole Molecular Hybrids as a Leading Edge in Drug Discovery: Current Landscape and Future Perspectives DOI
Suman Rohilla, Garima Goyal,

Paras Berwal

et al.

Current Topics in Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 24(18), P. 1557 - 1588

Published: May 20, 2024

Molecular hybridization is a rational design strategy used to create new ligands or prototypes by identifying and combining specific pharmacophoric subunits from the molecular structures of two more known bioactive derivatives. valuable technique in drug discovery, enabling modulation unwanted side effects creation potential dual-acting drugs that combine multiple therapeutic agents. Indole-triazole conjugates have emerged as promising candidates for development. The indole triazole moieties can be linked through various synthetic strategies, such click chemistry other coupling reactions, generate library diverse compounds biological screening. achievable structural diversity with indole-triazole offers avenues optimize their pharmacokinetic pharmacodynamic attributes, amplifying efficacy. Researchers extensively tailored both frameworks modifications comprehend impact on drug's characteristics. current review article endeavours explore discuss research strategies indoletriazole hybrids elucidate significance variety pathological conditions. insights provided herein are anticipated beneficial researchers will likely encourage further exploration this field.

Language: Английский

Citations

0
Uncovering Biased Signaling of Atypical Antipsychotics at Dopamine D3 Receptors in the Prefrontal Cortex DOI
Monserrat Avila-Zozaya

Biological Psychiatry, Journal Year: 2023, Volume and Issue: 94(7), P. e25 - e26

Published: Sept. 4, 2023

Language: Английский

Citations

0
Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket DOI Creative Commons
Javier García‐Nafría, Sandra Arroyo‐Urea,

Antonina Nazarova

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 19, 2023

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

Language: Английский

Citations

0