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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., Pazhamalil, J. G., Porebski, B. T., Pfleger, K. D. G., Lane, J. R., Canals, M., & 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., Carroll, D., Halls, M. L., Lane, J. R., Riedel, B., Ferrari, D., & 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., Shonberg, J., Scammells, P. J., Capuano, B., Sexton, P. M., Charlton, S. J., Javitch, J., Christopoulos, A., & 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., Christopoulos, A., Lane, J. R., & 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., Berginski, M. E., Huang, Z., Bear, J. E., Lane, J. R., Halls, M. L., Ferrari, D., Nowell, C. J., & 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., Christopoulos, A., Capuano, B., Scammells, P. J., & 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., Christopoulos, A., & 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., Shi, L., López, L., Scammells, P. J., Capuano, B., Sexton, P. M., Javitch, J. A., & 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., Sexton, P. M., & 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.