All Outputs (62)

Photo‐BQCA: Positive Allosteric Modulators Enabling Optical Control of the M1 Receptor (2024)
Journal Article
Gerwe, H., Schaller, E., Sortino, R., Opar, E., Martínez -Tambella, J., Bermudez, M., Lane, J. R., Gorostiza, P., & Decker, M. (2024). Photo‐BQCA: Positive Allosteric Modulators Enabling Optical Control of the M1 Receptor. Angewandte Chemie International Edition, 63(47), Article e202411438. https://doi.org/10.1002/anie.202411438

The field of G protein‐coupled receptor (GPCR) research has greatly benefited from the spatiotemporal resolution provided by light controllable, photoswitchable agents. Most of the developed tools have targeted the Rhodopsin‐like family (Class A), th... Read More about Photo‐BQCA: Positive Allosteric Modulators Enabling Optical Control of the M1 Receptor.

Enantioselective de novo synthesis of 14-hydroxy-6-oxomorphinans (2024)
Journal Article
Moore, J. C., Modell, L., Glenn, J. R., Jones, K. D., Argent, S. P., Lane, J. R., Canals, M., & Lam, H. W. (2024). Enantioselective de novo synthesis of 14-hydroxy-6-oxomorphinans. Chemical Communications, 60(47), 6007-6010. https://doi.org/10.1039/d4cc01788a

The enantioselective de novo synthesis of pharmacologically important 14-hydroxy-6-oxomorphinans is described. 4,5-Desoxynaltrexone and 4,5-desoxynaloxone were prepared using this route and their biological activities against the opioid receptors wer... Read More about Enantioselective de novo synthesis of 14-hydroxy-6-oxomorphinans.

In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling (2024)
Journal Article
Tsai, M.-H. M., Chen, L., Baumann, M. H., Canals, M., Javitch, J. A., Lane, J. R., & Shi, L. (2024). In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling. ACS Chemical Neuroscience, 15(4), 854-867. https://doi.org/10.1021/acschemneuro.3c00750

Novel synthetic opioids (NSOs), including both fentanyl and non-fentanyl analogs that act as μ-opioid receptor (MOR) agonists, are associated with serious intoxication and fatal overdose. Previous studies proposed that G-protein-biased MOR agonists a... Read More about In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling.

Discovery of the First‐in‐Class Inhibitors of Hypoxia Up‐Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation (2024)
Journal Article
Papadopoulou, D., Mavrikaki, V., Charalampous, F., Tzaferis, C., Samiotaki, M., Papavasileiou, K. D., Afantitis, A., Karagianni, N., Denis, M. C., Sanchez, J., Lane, R., Brotzakis, Z. F., Skretas, G., Georgiadis, D., Matralis, A. N., Kollias, G., Papavasileiou, K. D., Denis, M. C., & Matralis, A. N. (2024). Discovery of the First‐in‐Class Inhibitors of Hypoxia Up‐Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation. Angewandte Chemie International Edition, 63(14), Article e202319157. https://doi.org/10.1002/anie.202319157

Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to... Read More about Discovery of the First‐in‐Class Inhibitors of Hypoxia Up‐Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation.

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., Kruegel, A. C., Javitch, J. A., Lane, J. R., & 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.

OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including Gαz (2022)
Journal Article
Keen, A. C., Pedersen, M. H., Lemel, L., Scott, D. J., Canals, M., Littler, D. R., Beddoe, T., Ono, Y., Shi, L., Inoue, A., Javitch, J. A., & Lane, J. R. (2022). OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including Gαz. Communications Biology, 5(1), Article 256. https://doi.org/10.1038/s42003-022-03191-5

Heterotrimeric G proteins are the main signalling effectors for G protein-coupled receptors. Understanding the distinct functions of different G proteins is key to understanding how their signalling modulates physiological responses. Pertussis toxin,... Read More about OZITX, A pertussis toxin-like protein for occluding inhibitory G protein signalling including Gαz.

The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine (2022)
Journal Article
Hill, R., Kruegel, A. C., Javitch, J. A., Lane, J. R., & Canals, M. (2022). The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine. British Journal of Pharmacology, 179(14), 3875-3885. https://doi.org/10.1111/bph.15832

Background and Purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the μ opioid receptor. CYP3A-dependent oxidation of mitragynine yields the metabolite 7-OH mitragynine, a more efficacious μ receptor agon... Read More about The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine.

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., Schulz, S., & 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.

GRKs as Key Modulators of Opioid Receptor Function (2020)
Journal Article
Lemel, L., Lane, J. R., & Canals, M. (2020). GRKs as Key Modulators of Opioid Receptor Function. Cells, 9(11), Article 2400. https://doi.org/10.3390/cells9112400

Understanding the link between agonist-induced phosphorylation of the mu-opioid receptor (MOR) and the associated physiological effects is critical for the development of novel analgesic drugs and is particularly important for understanding the mecha... Read More about GRKs as Key Modulators of Opioid Receptor Function.

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., Manandhar, P., Santiago, M., Fritzwanker, S., Schmidel, F., Katte, T. A., Reekie, T., Grimsey, N. L., Kassiou, M., Kellam, B., Krasel, C., Halls, M. L., Connor, M., Lane, J. R., Schulz, S., …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., Verma, R. K., Lim, H. D., Yano, H., Javitch, J. A., & 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., Charlton, S. J., & 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., Draper-Joyce, C. J., Scammells, P. J., Christopoulos, A., Javitch, J. A., Capuano, B., Shi, L., & 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., Canals, M., & 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., Bohn, L. M., Neve, K. A., Kellendonk, C., & 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., Scammells, P. J., Lane, J. R., & 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., Moritz, A. E., Willette, B. K. A., Fyfe, T. J., Jain, P., Titus, S., Hazelwood, L. A., Aubé, J., Lane, J. R., Frankowski, K. J., & 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.