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

Anitha Kopinathan, Christopher Draper-Joyce, Monika Szabo, Arthur Christopoulos, Peter J. Scammells, J. Robert Lane, Ben Capuano

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy. Thus structural changes to this region of (1) allow the generation of a novel set of analogues with distinct pharmacological properties.

Original languageEnglish
Pages (from-to)371-377
Number of pages7
JournalJournal of Medicinal Chemistry
Volume62
Issue number1
DOIs
Publication statusPublished - 1 Oct 2019

Cite this

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title = "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",
abstract = "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 confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy. Thus structural changes to this region of (1) allow the generation of a novel set of analogues with distinct pharmacological properties.",
author = "Anitha Kopinathan and Christopher Draper-Joyce and Monika Szabo and Arthur Christopoulos and Scammells, {Peter J.} and Lane, {J. Robert} and Ben Capuano",
year = "2019",
month = "10",
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doi = "10.1021/acs.jmedchem.8b00192",
language = "English",
volume = "62",
pages = "371--377",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
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TY - JOUR

T1 - 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

AU - Kopinathan, Anitha

AU - Draper-Joyce, Christopher

AU - Szabo, Monika

AU - Christopoulos, Arthur

AU - Scammells, Peter J.

AU - Lane, J. Robert

AU - Capuano, Ben

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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 confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy. Thus structural changes to this region of (1) allow the generation of a novel set of analogues with distinct pharmacological properties.

AB - 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 confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy. Thus structural changes to this region of (1) allow the generation of a novel set of analogues with distinct pharmacological properties.

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U2 - 10.1021/acs.jmedchem.8b00192

DO - 10.1021/acs.jmedchem.8b00192

M3 - Article

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EP - 377

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -