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

Tim J Fyfe, Barbara Zarzycka, Herman D Lim, Barrie Kellam, Shailesh N Mistry, Vsevolod Katrich, Peter J Scammells, J Robert Lane, Ben Capuano

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Recently, a novel negative allosteric modulator (NAM) of the D2-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. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, whilst functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.

Original languageEnglish
Number of pages82
JournalJournal of Medicinal Chemistry
DOIs
Publication statusAccepted/In press - 2018

Cite this

@article{d5827994a62f48efadca0a7dacd83c56,
title = "A Thieno[2,3-d]pyrimidine Scaffold is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor",
abstract = "Recently, a novel negative allosteric modulator (NAM) of the D2-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. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, whilst functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.",
author = "Fyfe, {Tim J} and Barbara Zarzycka and Lim, {Herman D} and Barrie Kellam and Mistry, {Shailesh N} and Vsevolod Katrich and Scammells, {Peter J} and Lane, {J Robert} and Ben Capuano",
year = "2018",
doi = "10.1021/acs.jmedchem.7b01565",
language = "English",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",

}

A Thieno[2,3-d]pyrimidine Scaffold is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor. / Fyfe, Tim J; Zarzycka, Barbara; Lim, Herman D; Kellam, Barrie; Mistry, Shailesh N; Katrich, Vsevolod; Scammells, Peter J; Lane, J Robert; Capuano, Ben.

In: Journal of Medicinal Chemistry, 2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A Thieno[2,3-d]pyrimidine Scaffold is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor

AU - Fyfe, Tim J

AU - Zarzycka, Barbara

AU - Lim, Herman D

AU - Kellam, Barrie

AU - Mistry, Shailesh N

AU - Katrich, Vsevolod

AU - Scammells, Peter J

AU - Lane, J Robert

AU - Capuano, Ben

PY - 2018

Y1 - 2018

N2 - Recently, a novel negative allosteric modulator (NAM) of the D2-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. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, whilst functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.

AB - Recently, a novel negative allosteric modulator (NAM) of the D2-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. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, whilst functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.

UR - http://www.scopus.com/inward/record.url?scp=85046490671&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.7b01565

DO - 10.1021/acs.jmedchem.7b01565

M3 - Article

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

ER -