The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors

Verma, Ravi Kumar; Abramyan, Ara M.; Michino, Mayako; Free, R. Benjamin; Sibley, David R.; Javitch, Jonathan A.; Lane, J. Robert; Shi, Lei

doi:10.1371/journal.pcbi.1005948

All Outputs (7)

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.