Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand
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 allostery, focusing on modifications to three moieties...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
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American Chemical Society
2015
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| Online Access: | https://eprints.nottingham.ac.uk/30315/ |
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| author | Mistry, Shailesh N. Shonberg, Jeremy Draper-Joyce, Christopher J. Klein Herenbrink, Carmen Michino, Mayako Shi, Lei Christopoulos, Arthur Capuano, Ben Scammells, Peter J. Lane, J. Robert |
| author_facet | Mistry, Shailesh N. Shonberg, Jeremy Draper-Joyce, Christopher J. Klein Herenbrink, Carmen Michino, Mayako Shi, Lei Christopoulos, Arthur Capuano, Ben Scammells, Peter J. Lane, J. Robert |
| author_sort | Mistry, Shailesh N. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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 allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R. |
| first_indexed | 2025-11-14T19:08:38Z |
| format | Article |
| id | nottingham-30315 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:08:38Z |
| publishDate | 2015 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-303152020-05-04T17:15:22Z https://eprints.nottingham.ac.uk/30315/ Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand Mistry, Shailesh N. Shonberg, Jeremy Draper-Joyce, Christopher J. Klein Herenbrink, Carmen Michino, Mayako Shi, Lei Christopoulos, Arthur Capuano, Ben Scammells, Peter J. Lane, J. Robert 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 allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R. American Chemical Society 2015-08-10 Article PeerReviewed Mistry, Shailesh N., Shonberg, Jeremy, Draper-Joyce, Christopher J., Klein Herenbrink, Carmen, Michino, Mayako, Shi, Lei, Christopoulos, Arthur, Capuano, Ben, Scammells, Peter J. and Lane, J. Robert (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). pp. 6819-6843. ISSN 0022-2623 http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00585 doi:10.1021/acs.jmedchem.5b00585 doi:10.1021/acs.jmedchem.5b00585 |
| spellingShingle | Mistry, Shailesh N. Shonberg, Jeremy Draper-Joyce, Christopher J. Klein Herenbrink, Carmen Michino, Mayako Shi, Lei Christopoulos, Arthur Capuano, Ben Scammells, Peter J. Lane, J. Robert Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand |
| title | Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand |
| title_full | Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand |
| title_fullStr | Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand |
| title_full_unstemmed | Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand |
| title_short | Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand |
| title_sort | discovery of a novel class of negative allosteric modulator of the dopamine d2 receptor through fragmentation of a bitopic ligand |
| url | https://eprints.nottingham.ac.uk/30315/ https://eprints.nottingham.ac.uk/30315/ https://eprints.nottingham.ac.uk/30315/ |