scholarly journals 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 ◽  
Vol 58 (13) ◽  
pp. 5287-5307 ◽  
Author(s):  
Jeremy Shonberg ◽  
Christopher Draper-Joyce ◽  
Shailesh N. Mistry ◽  
Arthur Christopoulos ◽  
Peter J. Scammells ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Allosteric Modulator ◽  
Dopamine D2 ◽  
Structure Activity ◽  
Negative Allosteric Modulator

scholarly journals The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Christopher J. Draper-Joyce ◽  
Ravi Kumar Verma ◽  
Mayako Michino ◽  
Jeremy Shonberg ◽  
Anitha Kopinathan ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Allosteric Modulator ◽  
Sodium Ions ◽  
Dopamine D2 ◽  
Negative Allosteric Modulator

scholarly journals Evidence for Two Modes of Binding of the Negative Allosteric Modulator SB269,652 to the Dopamine D2 Receptor

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 22
Author(s):  
Richard Ågren ◽  
Kristoffer Sahlholm
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Binding Pocket ◽  
Binding Mode ◽  
Allosteric Modulator ◽  
Drug Candidates ◽  
Dopamine D2 ◽  
Inward Rectifier Potassium Channels ◽  
Negative Allosteric Modulator ◽  
G Protein Coupled

SB269,652 has been described as the first negative allosteric modulator (NAM) of the dopamine D2 receptor (D2R), however, the binding mode and allosteric mechanism of action of this ligand remain incompletely understood. SB269,652 comprises an orthosteric, primary pharmacophore and a secondary (or allosteric) pharmacophore joined by a hydrophilic cyclohexyl linker and is known to form corresponding interactions with the orthosteric binding site (OBS) and the secondary binding pocket (SBP) in the D2R. Here, we observed a surprisingly low potency of SB269,652 to negatively modulate the D2R-mediated activation of G protein-coupled inward-rectifier potassium channels (GIRK) and decided to perform a more detailed investigation of the interaction between dopamine and SB269,652. The results indicated that the SB269,652 inhibitory potency is increased 6.6-fold upon ligand pre-incubation, compared to the simultaneous co-application with dopamine. Mutagenesis experiments implicated both S193 in the OBS and E95 in the SBP in the effect of pre-application. The present findings extend previous knowledge about how SB269,652 competes with dopamine at the D2R and may be useful for the development of novel D2R ligands, such as antipsychotic drug candidates.

scholarly journals Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand

2015 ◽  
Vol 58 (17) ◽  
pp. 6819-6843 ◽  
Author(s):  
Shailesh N. Mistry ◽  
Jeremy Shonberg ◽  
Christopher J. Draper-Joyce ◽  
Carmen Klein Herenbrink ◽  
Mayako Michino ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Allosteric Modulator ◽  
Dopamine D2 ◽  
Negative Allosteric Modulator

scholarly journals A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor

2018 ◽  
Vol 62 (1) ◽  
pp. 174-206 ◽  
Author(s):  
Tim J. Fyfe ◽  
Barbara Zarzycka ◽  
Herman D. Lim ◽  
Barrie Kellam ◽  
Shailesh N. Mistry ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Allosteric Modulator ◽  
Dopamine D2 ◽  
Negative Allosteric Modulator

A Structure–Activity Analysis of Biased Agonism at the Dopamine D2 Receptor

2013 ◽  
Vol 56 (22) ◽  
pp. 9199-9221 ◽  
Author(s):  
Jeremy Shonberg ◽  
Carmen Klein Herenbrink ◽  
Laura López ◽  
Arthur Christopoulos ◽  
Peter J. Scammells ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Activity Analysis ◽  
Biased Agonism ◽  
Dopamine D2 ◽  
Structure Activity

An attempt at the hydrated imidazoline ring expansion (HIRE) of diarene-fused [1,4]diazepinones delivers selective dopamine D2 receptor ligands

Synthesis ◽  
2021 ◽  
Author(s):  
Sergey Grintsevich ◽  
Alexander V. Sapegin ◽  
Andrzej Bojarski ◽  
Beata Duszyńska ◽  
Mikhail Krasavin
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Ring Expansion ◽  
Side Chain ◽  
Receptor Ligands ◽  
Structure Activity Relationships ◽  
Dopamine D2 ◽  
Structure Activity ◽  
Imidazoline Ring ◽  
Selective Dopamine

Attempts to extend the hydrated imidazoline ring expansion (HIRE) strategy to a series of diarene-fused [1,4]diazepinones (earlier applied successfully to bis-pyrido substrate nevirapine) resulted in no ring expansion but rather 2-aminoethyl side chain expulsion. This seeming setback (setting the limitations to the HIRE methodology substrate scope) led to the discovery of selective dopamine D2 ligands with elements of structure-activity relationships.

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