Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D 2 receptor

Tim J. Fyfe, Barrie Kellam, Shailesh N. Mistry, Peter J. Scammells, J. Robert Lane, Ben Capuano

Research output: Contribution to journalArticleResearchpeer-review

Abstract

We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D 2 receptor (D 2 R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D 2 R including NAMs with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).

Original languageEnglish
Pages (from-to)474-490
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume168
DOIs
Publication statusPublished - 15 Apr 2019

Keywords

  • Agonists
  • Dopamine D receptor
  • NAMs
  • Negative allosteric modulators
  • Thieno[2,3-d]pyrimidines

Cite this

@article{c2a518c152204e1f9a91215fcd7a5e66,
title = "Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D 2 receptor",
abstract = "We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D 2 receptor (D 2 R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D 2 R including NAMs with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).",
keywords = "Agonists, Dopamine D receptor, NAMs, Negative allosteric modulators, Thieno[2,3-d]pyrimidines",
author = "Fyfe, {Tim J.} and Barrie Kellam and Mistry, {Shailesh N.} and Scammells, {Peter J.} and Lane, {J. Robert} and Ben Capuano",
year = "2019",
month = "4",
day = "15",
doi = "10.1016/j.ejmech.2019.01.061",
language = "English",
volume = "168",
pages = "474--490",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier",

}

Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D 2 receptor. / Fyfe, Tim J.; Kellam, Barrie; Mistry, Shailesh N.; Scammells, Peter J.; Lane, J. Robert; Capuano, Ben.

In: European Journal of Medicinal Chemistry, Vol. 168, 15.04.2019, p. 474-490.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D 2 receptor

AU - Fyfe, Tim J.

AU - Kellam, Barrie

AU - Mistry, Shailesh N.

AU - Scammells, Peter J.

AU - Lane, J. Robert

AU - Capuano, Ben

PY - 2019/4/15

Y1 - 2019/4/15

N2 - We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D 2 receptor (D 2 R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D 2 R including NAMs with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).

AB - We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D 2 receptor (D 2 R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D 2 R including NAMs with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).

KW - Agonists

KW - Dopamine D receptor

KW - NAMs

KW - Negative allosteric modulators

KW - Thieno[2,3-d]pyrimidines

UR - http://www.scopus.com/inward/record.url?scp=85062282492&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2019.01.061

DO - 10.1016/j.ejmech.2019.01.061

M3 - Article

VL - 168

SP - 474

EP - 490

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -