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ROB LANE's Outputs (55)

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice (2023)
Journal Article
Hill, R., Sanchez, J., Lemel, L., Antonijevic, M., Hosking, Y., Mistry, S. N., …Canals, M. (2023). Assessment of the potential of novel and classical opioids to induce respiratory depression in mice. British Journal of Pharmacology, 180(24), 3160-3174. https://doi.org/10.1111/bph.16199

Background and Purpose
Opioid-induced respiratory depression limits the use of μ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respira... Read More about Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.

Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10 (2021)
Journal Article
Lim, H. D., Robert Lane, J., Canals, M., & Stone, M. J. (2021). Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10. International Journal of Molecular Sciences, 22(8), Article 4232. https://doi.org/10.3390/ijms22084232

Chemokines interact with chemokine receptors in a promiscuous network, such that each receptor can be activated by multiple chemokines. Moreover, different chemokines have been reported to preferentially activate different signalling pathways via the... Read More about Systematic assessment of chemokine signaling at chemokine receptors ccr4, ccr7 and ccr10.

New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling (2021)
Journal Article
Mann, A., Keen, A. C., Mark, H., Dasgupta, P., Javitch, J. A., Canals, M., …Robert Lane, J. (2022). New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling. Scientific Reports, 11(1), Article 8288. https://doi.org/10.1038/s41598-021-87417-2

The dopamine D2 receptor (D2R) is the target of drugs used to treat the symptoms of Parkinson’s disease and schizophrenia. The D2R is regulated through its interaction with and phosphorylation by G protein receptor kinases (GRKs) and interaction with... Read More about New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling.

Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists (2020)
Journal Article
Gillis, A., Gondin, A. B., Kliewer, A., Sanchez, J., Lim, H. D., Alamein, C., …Canals, M. (2020). Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists. Science Signaling, 13(625), Article eaaz3140. https://doi.org/10.1126/scisignal.aaz3140

Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of... Read More about Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists.

Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism (2020)
Journal Article
Lane, J. R., Abramyan, A. M., Adhikari, P., Keen, A. C., Lee, K.-H., Sanchez, J., …Shi, L. (2020). Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism. eLife, 9, Article e52189. https://doi.org/10.7554/elife.52189

By analyzing and simulating inactive conformations of the highly-homologous dopamine D2 and D3 receptors (D2R and D3R), we find that eticlopride binds D2R in a pose very similar to that in the D3R/eticlopride structure but incompatible with the D2R/r... Read More about Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism.

Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor (2019)
Journal Article
Fyfe, T. J., Kellam, B., Sykes, D. A., Capuano, B., Scammells, P. J., Lane, J. R., …Mistry, S. N. (2019). Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor. Journal of Medicinal Chemistry, 62(21), 9488-9520. https://doi.org/10.1021/acs.jmedchem.9b00864

Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side-effects (EPS) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with c... Read More about Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor.

Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole (2019)
Journal Article
Klein Herenbrink, C., Verma, R., Lim, H. D., Kopinathan, A., Keen, A., Shonberg, J., …Lane, J. R. (2019). Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole. ACS Chemical Biology, 14(8), 1780-1792. https://doi.org/10.1021/acschembio.9b00342

Partial agonists of the dopamine D2 receptor (D2R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such dru... Read More about Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.

Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor (2019)
Journal Article
Fyfe, T. J., Kellam, B., Mistry, S. N., Scammells, P. J., Lane, J. R., & Capuano, B. (2019). Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor. European Journal of Medicinal Chemistry, 168, 474-490. https://doi.org/10.1016/j.ejmech.2019.01.061

We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like N... Read More about Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor.

Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1 (2018)
Journal Article
Sanchez, J., e Huma, Z., Lane, J., Liu, X., Bridgford, J. L., Payne, R. J., …Stone, M. J. (2018). Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1. Journal of Biological Chemistry, 294(10), 3464-3475. https://doi.org/10.1074/jbc.ra118.006535

© 2019 Sanchez et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. Interactions between secreted immune proteins called chemokines and their cognate G protein– coupled receptors regulate the t... Read More about Evaluation and extension of the two-site, two-step model for binding and activation of the chemokine receptor CCR1.

Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation (2018)
Journal Article
Donthamsetti, P., Gallo, E. F., Buck, D. C., Stahl, E. L., Zhu, Y., Lane, J. R., …Javitch, J. A. (2018). Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. Molecular Psychiatry, 25, 2086–2100. https://doi.org/10.1038/s41380-018-0212-4

The dopamine (DA) D2 receptor (D2R) is an important target for the treatment of neuropsychiatric disorders such as schizophrenia and Parkinson's disease. However, the development of improved therapeutic strategies has been hampered by our incomplete... Read More about Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation.

Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator N-(( trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1 H)-yl)ethyl)cyclohexyl)-1 H-indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D2 Receptor (2018)
Journal Article
Kopinathan, A., Draper-Joyce, C., Szabo, M., Christopoulos, A., Scammells, P. J., Lane, J. R., & Capuano, B. (2019). Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator N-(( trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1 H)-yl)ethyl)cyclohexyl)-1 H-indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D2 Receptor. Journal of Medicinal Chemistry, 62(1), 371-377. https://doi.org/10.1021/acs.jmedchem.8b00192

SB269652 (1) is a negative allosteric modulator of the dopamine D2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of "second generation" analogues of 1 whereby subtle modifications to the indole-2-carboxamide motif... Read More about Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator N-(( trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1 H)-yl)ethyl)cyclohexyl)-1 H-indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D2 Receptor.

A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor (2018)
Journal Article
Fyfe, T. J., Zarzycka, B., Lim, H. D., Kellam, B., Mistry, S. N., Katrich, V., …Capuano, B. (2019). A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor. Journal of Medicinal Chemistry, 62(1), 174–206. https://doi.org/10.1021/acs.jmedchem.7b01565

Recently, a novel negative allosteric modulator (NAM) of the D 2-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3-d]pyrimidine scaffold that does not feature in known dopaminergic ligands.... Read More about A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor.

Identification of Positive Allosteric Modulators of the D1 Dopamine Receptor That Act at Diverse Binding Sites (2018)
Journal Article
Luderman, K. D., Conroy, J. L., Free, R. B., Southall, N., Ferrer, M., Sanchez-Soto, M., …Sibley, D. R. (2018). Identification of Positive Allosteric Modulators of the D1 Dopamine Receptor That Act at Diverse Binding Sites. Molecular Pharmacology, 94(4), 1197-1209. https://doi.org/10.1124/mol.118.113175

The D1 dopamine receptor is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition in schizophrenia, Alzheimer disease, and other disorders. Positive allosteric modulators (PAMs), w... Read More about Identification of Positive Allosteric Modulators of the D1 Dopamine Receptor That Act at Diverse Binding Sites.

The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions (2018)
Journal Article
Draper-Joyce, C. J., Verma, R. K., Michino, M., Shonberg, J., Kopinathan, A., Herenbrink, C., …Lane, J. R. (2018). The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions. Scientific Reports, 8(1), Article 1208. https://doi.org/10.1038/s41598-018-19642-1

© 2018 The Author(s). Sodiumions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D 2 receptor (D 2 R). Experimental and computational evidences have... Read More about The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions.

The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors (2018)
Journal Article
Verma, R. K., Abramyan, A. M., Michino, M., Free, R. B., Sibley, D. R., Javitch, J. A., …Shi, L. (2018). The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors. PLoS Computational Biology, 14(1), Article e1005948. https://doi.org/10.1371/journal.pcbi.1005948

The dopamine D2 and D3 receptors (D2R and D3R) are important targets for antipsychotics and for the treatment of drug abuse. SB269652, a bitopic ligand that simultaneously binds both the orthosteric binding site (OBS) and a secondary binding pocket (... Read More about The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors.

Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors (2017)
Journal Article
Sykes, D. A., Moore, H., Stott, L., Holliday, N., Javitch, J. A., Lane, J. R., & Charlton, S. J. (2017). Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nature Communications, 8(1), Article 763. https://doi.org/10.1038/s41467-017-00716-z

Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor. However, support for this hypothesis is limited to a relatively small number o... Read More about Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors.

Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2 (2017)
Journal Article
Huma, Z. E., Sanchez, J., Lim, H. D., Bridgford, J. L., Huang, C., Parker, B. J., …Stone, M. J. (2017). Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2. Science Signaling, 10(480), Article eaai8529. https://doi.org/10.1126/scisignal.aai8529

Chemokines and their receptors collectively orchestrate the trafficking of leukocytes in normal immune function and inflammatory diseases. Different chemokines can induce distinct responses at the same receptor. In comparison to monocyte chemoattract... Read More about Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2.

Multivalent approaches and beyond: novel tools for the investigation of dopamine D2 receptor pharmacology (2016)
Journal Article
Kopinathan, A., Scammells, P. J., Lane, J. R., & Capuano, B. (2016). Multivalent approaches and beyond: novel tools for the investigation of dopamine D2 receptor pharmacology. Future Medicinal Chemistry, 8(11), 1349-1372. https://doi.org/10.4155/fmc-2016-0010

The dopamine D2 receptor (D2R) has been implicated in the symptomology of disorders such as schizophrenia and Parkinson's disease. Multivalent ligands provide useful tools to investigate emerging concepts of G protein-coupled receptor drug action suc... Read More about Multivalent approaches and beyond: novel tools for the investigation of dopamine D2 receptor pharmacology.

β2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer (2016)
Journal Article
Chang, A., Le, C. P., Walker, A. K., Creed, S. J., Pon, C. K., Albold, S., …Sloan, E. K. (2016). β2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer. Brain, Behavior, and Immunity, 57, 106-115. https://doi.org/10.1016/j.bbi.2016.06.011

© 2016 The Authors Chronic stress accelerates metastasis – the main cause of death in cancer patients – through the activation of β-adrenoceptors (βARs). We have previously shown that β2AR signaling in MDA-MB-231HM breast cancer cells, facilitates in... Read More about β2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer.

The role of kinetic context in apparent biased agonism at GPCRs (2016)
Journal Article
Javitch, J. A., Klein Herenbrink, C., Sykes, D. A., Donthamsetti, P., Canals, M., Coudrat, T., …Lane, J. R. (2016). The role of kinetic context in apparent biased agonism at GPCRs. Nature Communications, 7, Article 10842. https://doi.org/10.1038/ncomms10842

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usu... Read More about The role of kinetic context in apparent biased agonism at GPCRs.

4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor (2015)
Journal Article
Mistry, S. N., Jörg, M., Lim, H., Vinh, N. B., Sexton, P. M., Capuano, B., …Scammells, P. J. (2016). 4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor. Journal of Medicinal Chemistry, 59(1), 388-409. https://doi.org/10.1021/acs.jmedchem.5b01562

Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimer’s and schizophrenia. Herein, we report the... Read More about 4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor.

β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion (2015)
Journal Article
Creed, S. J., Le, C. P., Hassan, M., Pon, C. K., Albold, S., Chan, K. T., …Sloan, E. K. (2015). β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion. Breast Cancer Research, 17(1), Article 145. https://doi.org/10.1186/s13058-015-0655-3

INTRODUCTION:For efficient metastatic dissemination, tumor cells form invadopodia to degrade and move through three-dimensional extracellular matrix. However, little is known about the conditions that favor invadopodia formation. Here, we investigate... Read More about β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion.

The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion (2015)
Journal Article
Pon, C. K., Lane, J. R., Sloan, E. K., & Halls, M. L. (2016). The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion. FASEB Journal, 30(3), 1144-1154. https://doi.org/10.1096/fj.15-277798

Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates β-adrenoceptors (βARs) to enhance metastasis from primary tumors and that β-blockers may be protectiv... Read More about The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion.

A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor (2015)
Journal Article
Szabo, M., Huynh, T., Valant, C., Lane, J. R., Sexton, P. M., Christopoulos, A., & Capuano, B. (2015). A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor. MedChemComm, 6(11), 1998-2003. https://doi.org/10.1039/C5MD00334B

Positive allosteric modulators (PAMs) targeting the M4 muscarinic acetylcholine receptor (mAChR) offer greater sub-type selectivity and unique potential as central nervous system agents through their novel mode of action to traditional orthosteric li... Read More about A structure-activity relationship study of the positive allosteric modulator LY2033298 at the M4 muscarinic acetylcholine receptor.

Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand (2015)
Journal Article
Mistry, S. N., Shonberg, J., Draper-Joyce, C. J., Klein Herenbrink, C., Michino, M., Shi, L., …Lane, J. R. (2015). Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand. Journal of Medicinal Chemistry, 58(17), 6819-6843. https://doi.org/10.1021/acs.jmedchem.5b00585

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allo... Read More about Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand.

Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor (2015)
Journal Article
Thompson, G. L., Lane, J. R., Coudrat, T., Sexton, P. M., Christopoulos, A., & Canals, M. (2015). Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor. Molecular Pharmacology, 88(2), 335-346. https://doi.org/10.1124/mol.115.098848

Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Biased agonism is having a major impact on modern drug discovery, and describes the ability of distinct G protein-coupled receptor (GPCR) ligands to activate dif... Read More about Biased Agonism of Endogenous Opioid Peptides at the μ-Opioid Receptor.

Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor (2015)
Journal Article
Shonberg, J., Draper-Joyce, C., Mistry, S. N., Christopoulos, A., Scammells, P. J., Lane, J. R., & Capuano, B. (2015). Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor. Journal of Medicinal Chemistry, 58(13), 5287-5307. https://doi.org/10.1021/acs.jmedchem.5b00581

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allo... Read More about Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor.

Proof of concept study for designed multiple ligands targeting the dopamine D2, serotonin 5-HT2A, and muscarinic M1 acetylcholine receptors (2015)
Journal Article
Szabo, M., Lim, H. D., Herenbrink, C. K., Christopoulos, A., Lane, J. R., & Capuano, B. (2015). Proof of concept study for designed multiple ligands targeting the dopamine D2, serotonin 5-HT2A, and muscarinic M1 acetylcholine receptors. Journal of Medicinal Chemistry, 58(3), 1550-1555. https://doi.org/10.1021/jm5013243

Herein we describe the hybridization of a benzoxazinone M1 scaffold with D2 privileged structures derived from putative and clinically relevant antipsychotics to develop designed multiple ligands. The M1 mAChR is an attractive target for the cognitiv... Read More about Proof of concept study for designed multiple ligands targeting the dopamine D2, serotonin 5-HT2A, and muscarinic M1 acetylcholine receptors.

Mechanistic Insights into Allosteric Structure-Function Relationships at the M1 Muscarinic Acetylcholine Receptor (2014)
Journal Article
Abdul-Ridha, A., Lane, J. R., Mistry, S. N., Lopez, L., Sexton, P. M., Scammells, P. J., …Canals, M. (2014). Mechanistic Insights into Allosteric Structure-Function Relationships at the M1 Muscarinic Acetylcholine Receptor. Journal of Biological Chemistry, 289(48), 33701-33711. https://doi.org/10.1074/jbc.m114.604967

Benzylquinolone carboxylic acid (BQCA) is the first highly selective positive allosteric modulator (PAM) for the M1 muscarinic acetylcholine receptor (mAChR), but it possesses low affinity for the allosteric site on the receptor. More recent drug dis... Read More about Mechanistic Insights into Allosteric Structure-Function Relationships at the M1 Muscarinic Acetylcholine Receptor.

A new mechanism of allostery in a G protein-coupled receptor dimer (2014)
Journal Article
Lane, J. R., Donthamsetti, P., Shonberg, J., Draper-Joyce, C. J., Dentry, S., Michino, M., …Christopoulos, A. (2014). A new mechanism of allostery in a G protein-coupled receptor dimer. Nature Chemical Biology, 10(9), 745-752. https://doi.org/10.1038/nchembio.1593

SB269652 is to our knowledge the first drug-like allosteric modulator of the dopamine D2 receptor (D2R), but it contains structural features associated with orthosteric D2R antagonists. Using a functional complementation system to control the identit... Read More about A new mechanism of allostery in a G protein-coupled receptor dimer.

Molecular Mechanisms of Bitopic Ligand Engagement with the M1 Muscarinic Acetylcholine Receptor (2014)
Journal Article
Keov, P., Lopez, L., Devine, S. M., Valant, C., Lane, J. R., Scammells, P. J., …Christopoulos, A. (2014). Molecular Mechanisms of Bitopic Ligand Engagement with the M1 Muscarinic Acetylcholine Receptor. Journal of Biological Chemistry, 289(34), 23817-23837. https://doi.org/10.1074/jbc.M114.582874

TBPB and 77-LH-28-1 are selective agonists of the M1 muscarinic acetylcholine receptor (mAChR) that may gain their selectivity through a bitopic mechanism, interacting concomitantly with the orthosteric site and part of an allosteric site. The curren... Read More about Molecular Mechanisms of Bitopic Ligand Engagement with the M1 Muscarinic Acetylcholine Receptor.

Structure–Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D 2Receptor (2014)
Journal Article
Szabo, M., Klein Herenbrink, C., Christopoulos, A., Lane, J. R., & Capuano, B. (2014). Structure–Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D 2Receptor. Journal of Medicinal Chemistry, 57(11), 4924-4939. https://doi.org/10.1021/jm500457x

Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D2 receptor (D2R). We investigated the determinants of efficacy, affini... Read More about Structure–Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D 2Receptor.

Biased Agonism at G Protein‐Coupled Receptors: The Promise and the Challenges—A Medicinal Chemistry Perspective (2014)
Journal Article
Shonberg, J., Christopoulos, A., Lopez, L., Scammells, P. J., Capuano, B., & Lane, J. R. (2014). Biased Agonism at G Protein‐Coupled Receptors: The Promise and the Challenges—A Medicinal Chemistry Perspective. Medicinal Research Reviews, 34(6), 1286-1330. https://doi.org/10.1002/med.21318

Historically, determination of G protein‐coupled receptor (GPCR) ligand efficacy has often been restricted to identifying the ligand as an agonist or antagonist at a given signaling pathway. This classification was deemed sufficient to predict compou... Read More about Biased Agonism at G Protein‐Coupled Receptors: The Promise and the Challenges—A Medicinal Chemistry Perspective.

Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor (2014)
Journal Article
Abdul-Ridha, A., López, L., Keov, P., Thal, D. M., Mistry, S. N., Sexton, P. M., …Christopoulos, A. (2014). Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor. Journal of Biological Chemistry, 289(9), 6067-6079. https://doi.org/10.1074/jbc.M113.539080

Benzylquinolone carboxylic acid (BQCA) is an unprecedented example of a selective positive allosteric modulator of acetylcholine at the M1 muscarinic acetylcholine receptor (mAChR). To probe the structural basis underlying its selectivity, we utilize... Read More about Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor.

A structure-activity analysis of biased agonism at the dopamine D2 receptor. (2013)
Journal Article
Shonberg, J., Herenbrink, C. K., López, L., Christopoulos, A., Scammells, P. J., Capuano, B., & Lane, J. R. (2013). A structure-activity analysis of biased agonism at the dopamine D2 receptor. Journal of Medicinal Chemistry, 56(22), 9199-9221. https://doi.org/10.1021/jm401318w

Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsy... Read More about A structure-activity analysis of biased agonism at the dopamine D2 receptor..

Reverse Engineering of the Selective Agonist TBPB Unveils Both Orthosteric and Allosteric Modes of Action at the M1 Muscarinic Acetylcholine Receptor (2013)
Journal Article
Keov, P., Valant, C., Devine, S. M., Lane, J. R., Scammells, P. J., Sexton, P. M., & Christopoulos, A. (2013). Reverse Engineering of the Selective Agonist TBPB Unveils Both Orthosteric and Allosteric Modes of Action at the M1 Muscarinic Acetylcholine Receptor. Molecular Pharmacology, 84(3), 425-437. https://doi.org/10.1124/mol.113.087320

Recent interest in the M1 muscarinic acetylcholine (ACh) receptor (mAChR) has led to the discovery of various selective agonists for the receptor. The novel selective agonist 1-(1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1 (... Read More about Reverse Engineering of the Selective Agonist TBPB Unveils Both Orthosteric and Allosteric Modes of Action at the M1 Muscarinic Acetylcholine Receptor.

Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor (2013)
Journal Article
Shonberg, J., Lane, J. R., Scammells, P. J., & Capuano, B. (2013). Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor. MedChemComm, 4(9), 1290-1296. https://doi.org/10.1039/c3md00154g

Bivalent ligands represent useful tools to investigate the phenomenon of GPCR dimerization. We synthesized bivalent ligands based on (R)-apomorphine with variations in spacer length, and assessed these compounds in functional and binding assays at th... Read More about Synthesis, functional and binding profile of (R)-apomorphine based homobivalent ligands targeting the dopamine D2 receptor.

Bridging the gap: bitopic ligands of G-protein-coupled receptors (2012)
Journal Article
Lane, J. R., Sexton, P. M., & Christopoulos, A. (2013). Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends in Pharmacological Sciences, 34(1), 59-66. https://doi.org/10.1016/j.tips.2012.10.003

Although classical approaches to G-protein-coupled receptor (GPCR) drug design have targeted the orthosteric binding site, potentially all GPCRs possess druggable allosteric sites. In addition, it is clear that GPCRs can adopt multiple active states... Read More about Bridging the gap: bitopic ligands of G-protein-coupled receptors.

Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A) (2010)
Journal Article
van Veldhoven, J. P. D., Blad, C. C., Artsen, C. M., Klopman, C., Wolfram, D. R., Abdelkadir, M. J., …IJzerman, A. P. (2011). Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A). Bioorganic and Medicinal Chemistry, 21(9), 2736-2739. https://doi.org/10.1016/j.bmcl.2010.11.091

Nicotinic acid (niacin) has been used for decades as an antidyslipidemic drug in man. Its main target is the hydroxy-carboxylic acid receptor HCA2 (GPR109A), a G protein-coupled receptor. Other acids and esters such as methyl fumarate also interact w... Read More about Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A).

Characterization of [3H]LUF5834: A novel non-ribose high-affinity agonist radioligand for the adenosine A1 receptor (2010)
Journal Article
Lane, J. R., Klaasse, E., Lin, J., van Bruchem, J., Beukers, M. W., & Ijzerman, A. P. (2010). Characterization of [3H]LUF5834: A novel non-ribose high-affinity agonist radioligand for the adenosine A1 receptor. Biochemical Pharmacology, 80(8), 1180-1189. https://doi.org/10.1016/j.bcp.2010.06.041

The adenosine A(1) receptor is a promising therapeutic target for neurological disorders such as cognition deficits and is involved in cardiovascular preconditioning. Classically adenosine receptor agonists were all derivatives of adenosine, and thou... Read More about Characterization of [3H]LUF5834: A novel non-ribose high-affinity agonist radioligand for the adenosine A1 receptor.

Hybrid ortho/allosteric ligands for the adenosine A(1) receptor (2010)
Journal Article
Narlawar, R., Lane, J. R., Doddareddy, M., Lin, J., Brussee, J., & Ijzerman, A. P. (2010). Hybrid ortho/allosteric ligands for the adenosine A(1) receptor. Journal of Medicinal Chemistry, 53(8), 3028-3037. https://doi.org/10.1021/jm901252a

Many G protein-coupled receptors (GPCRs), including the adenosine A(1) receptor (A(1)AR), have been shown to be allosterically modulated by small molecule ligands. So far, in the absence of structural information, the exact location of the allosteric... Read More about Hybrid ortho/allosteric ligands for the adenosine A(1) receptor.

Structure-Based Discovery of Novel Chemotypes for Adenosine A2A Receptor Antagonists (2010)
Journal Article
Katritch, V., Jaakola, V., Lane, J. R., Lin, J., Ijzerman, A. P., Yeager, M., …Abagyan, R. (2010). Structure-Based Discovery of Novel Chemotypes for Adenosine A2A Receptor Antagonists. Journal of Medicinal Chemistry, 53(4), 1799-1809. https://doi.org/10.1021/jm901647p

The recent progress in crystallography of G-protein coupled receptors opens an unprecedented venue for structure-based GPCR drug discovery. To test efficiency of the structure-based approach, we performed molecular docking and virtual ligand screenin... Read More about Structure-Based Discovery of Novel Chemotypes for Adenosine A2A Receptor Antagonists.

Ligand binding and subtype selectivity of the human A(2A) adenosine receptor: identification and characterization of essential amino acid residues (2010)
Journal Article
Jaakola, V., Lane, J. R., Lin, J. Y., Katritch, V., Ijzerman, A. P., & Stevens, R. C. (2010). Ligand binding and subtype selectivity of the human A(2A) adenosine receptor: identification and characterization of essential amino acid residues. Journal of Biological Chemistry, 285(17), 13032-13044. https://doi.org/10.1074/jbc.M109.096974

The crystal structure of the human A(2A) adenosine receptor bound to the A(2A) receptor-specific antagonist, ZM241385, was recently determined at 2.6-A resolution. Surprisingly, the antagonist binds in an extended conformation, perpendicular to the p... Read More about Ligand binding and subtype selectivity of the human A(2A) adenosine receptor: identification and characterization of essential amino acid residues.

A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization (2010)
Journal Article
van der Horst, E., Peironcely, J. E., Ijzerman, A. P., Beukers, M. W., Lane, J. R., van Vlijmen, H. W. T., …Bender, A. (2010). A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization. BMC Bioinformatics, 11, Article 316. https://doi.org/10.1186/1471-2105-11-316

BACKGROUND:G protein-coupled receptors (GPCRs) represent a family of well-characterized drug targets with significant therapeutic value. Phylogenetic classifications may help to understand the characteristics of individual GPCRs and their subtypes. P... Read More about A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization.

The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor (2009)
Journal Article
Lane, J. R., Beukers, M. W., Mulder-Krieger, T., & IJzerman, A. P. (2010). The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor. Biochemical Pharmacology, 79(1), 48-56. https://doi.org/10.1016/j.bcp.2009.07.024

Studies of endogenous cannabinoid agonists, such as 2-arachidonylglycerol (2-AG), have revealed their potential to exert modulatory actions on other receptor systems in addition to their ability to activate cannabinoid receptors. This study investiga... Read More about The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor.

The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist (2008)
Journal Article
Jaakola, V., Griffith, M. T., Hanson, M. A., Cherezov, V., Chien, E. Y. T., Lane, J. R., …Stevens, R. C. (2008). The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science, 322(5905), 1211-1217. https://doi.org/10.1126/science.1164772

The adenosine class of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) mediates the important role of extracellular adenosine in many physiological processes and is antagonized by caffeine. We have determined t... Read More about The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist.

G Protein Coupling and Ligand Selectivity of the D2L and D3 Dopamine Receptors (2008)
Journal Article
Lane, J. R., Powney, B., Wise, A., Rees, S., & Milligan, G. (2008). G Protein Coupling and Ligand Selectivity of the D2L and D3 Dopamine Receptors. Journal of Pharmacology and Experimental Therapeutics, 325(1), 319-330. https://doi.org/10.1124/jpet.107.134296

The human dopamine D2L receptor couples promiscuously to multiple members of the Gαi/o subfamily. Despite the high homology of the D2L and D3 receptors, the G protein coupling specificity of the human D3 receptor is less clearly characterized. The pr... Read More about G Protein Coupling and Ligand Selectivity of the D2L and D3 Dopamine Receptors.

Antibodies that identify only the active conformation of G(i) family G protein alpha subunits (2008)
Journal Article
Lane, J. R., Henderson, D., Powney, B., Wise, A., Rees, S., Daniels, D., …Milligan, G. (2008). Antibodies that identify only the active conformation of G(i) family G protein alpha subunits. FASEB Journal, 22(6), 1924-1932. https://doi.org/10.1096/fj.07-100388

Production of antisera able to recognize individual heterotrimeric G protein alpha subunits resulted in rapid expansion of information on their distribution and function. However, no antibodies that specifically recognize the active state have been a... Read More about Antibodies that identify only the active conformation of G(i) family G protein alpha subunits.

Novel pharmacological applications of G-protein-coupled receptor-G protein fusions (2007)
Journal Article
Milligan, G., Parenty, G., Stoddart, L. A., & Lane, J. R. (2007). Novel pharmacological applications of G-protein-coupled receptor-G protein fusions. Current Opinion in Pharmacology, 7(5), 521-526. https://doi.org/10.1016/j.coph.2007.06.007

Single, bi-functional polypeptides consisting of a G-protein-coupled receptor (GPCR) linked directly to a G protein alpha subunit have been employed for a number of years to study many aspects of signal initiation, including the roles of post-transla... Read More about Novel pharmacological applications of G-protein-coupled receptor-G protein fusions.

Protean agonism at the dopamine D2 receptor: (S)-3-(3-hydroxyphenyl)-N-propylpiperidine is an agonist for activation of Go1 but an antagonist/inverse agonist for Gi1,Gi2, and Gi3 (2007)
Journal Article
Lane, J. R., Powney, B., Wise, A., Rees, S., & Milligan, G. (2007). Protean agonism at the dopamine D2 receptor: (S)-3-(3-hydroxyphenyl)-N-propylpiperidine is an agonist for activation of Go1 but an antagonist/inverse agonist for Gi1,Gi2, and Gi3. Molecular Pharmacology, 71(5), 1349-1359. https://doi.org/10.1124/mol.106.032722

A range of ligands displayed agonism at the long isoform of the human dopamine D(2) receptor, whether using receptor-G protein fusions or membranes of cells in which pertussis toxin-resistant mutants of individual Galpha(i)-family G proteins could be... Read More about Protean agonism at the dopamine D2 receptor: (S)-3-(3-hydroxyphenyl)-N-propylpiperidine is an agonist for activation of Go1 but an antagonist/inverse agonist for Gi1,Gi2, and Gi3.