Discovery of a novel class of negative allosteric modulator of the dopamine D2 receptor through fragmentation of a bitopic ligand

Shailesh Natvarbhai Mistry, Jeremy Shonberg, Christopher James Draper-Joyce, Carmen Klein Herenbrink, Mayako Michino, Lei Shi, Arthur Christopoulos, Benvenuto Capuano, Peter John Scammells, Jonathan Robert David Lane

Research output: Contribution to journalArticleResearchpeer-review

37 Citations (Scopus)

Abstract

Recently, we have demonstrated that N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) (1) adopts a bitopic pose at one protomer of a dopamine D2 receptor (D2R) dimer to negatively modulate the binding of dopamine at the other protomer. The 1H-indole-2-carboxamide moiety of 1 extends into a secondary pocket between the extracellular ends of TM2 and TM7 within the D2R protomer. To target this putative allosteric site, we generated and characterized fragments that include and extend from the 1H-indole-2-carboxamide moiety of 1. N-Isopropyl-1H-indole-2-carboxamide (3) displayed allosteric pharmacology and sensitivity to mutations of the same residues at the top of TM2 as was observed for 1. Using 3 as an "allosteric lead", we designed and synthesized an extensive fragment library to generate novel SAR and identify N-butyl-1H-indole-2-carboxamide (11d), which displayed both increased negative cooperativity and affinity for the D2R. These data illustrate that fragmentation of extended compounds can expose fragments with purely allosteric pharmacology.
Original languageEnglish
Pages (from-to)6819-6843
Number of pages25
JournalJournal of Medicinal Chemistry
Volume58
Issue number17
DOIs
Publication statusPublished - 2015

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