Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand

Shailesh N Mistry; Jeremy Shonberg; Christopher J Draper-Joyce; Carmen Klein Herenbrink; Mayako Michino; Lei Shi; Arthur Christopoulos; Ben Capuano; Peter J Scammells; J Robert Lane

doi:10.1021/acs.jmedchem.5b00585

Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand

J Med Chem. 2015 Sep 10;58(17):6819-43. doi: 10.1021/acs.jmedchem.5b00585. Epub 2015 Aug 28.

Affiliations

¹ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
² Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
³ Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , Baltimore, Maryland 21224, United States.
⁴ Department of Physiology and Biophysics, Weill Medical College of Cornell University , New York, New York 10065, United States.
⁵ Institute for Computational Biomedicine, Weill Medical College of Cornell University , New York, New York 10021, United States.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Amides / chemical synthesis
Amides / chemistry*
Amides / pharmacology
Animals
Arrestins / metabolism
CHO Cells
Corpus Striatum / metabolism
Cricetulus
Dopamine Agents / chemical synthesis
Dopamine Agents / chemistry*
Dopamine Agents / pharmacology
GTP-Binding Proteins / metabolism
HEK293 Cells
Humans
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology
Isoquinolines / chemical synthesis
Isoquinolines / chemistry
Isoquinolines / pharmacology
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Mutation
Phosphorylation
Radioligand Assay
Rats
Receptors, Dopamine D2 / genetics
Receptors, Dopamine D2 / metabolism*
Stereoisomerism
Structure-Activity Relationship
beta-Arrestins

Substances

1H-indole-2-carboxylic acid (4-(2-(cyano-3,4-dihydro-1H-isoquinolin-2-yl)ethyl)cyclohexyl)amide
Amides
Arrestins
Dopamine Agents
Indoles
Isoquinolines
N-butyl-1H-indole-2-carboxamide
Receptors, Dopamine D2
beta-Arrestins
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
GTP-Binding Proteins

Grants and funding

ZIA DA000606/ImNIH/Intramural NIH HHS/United States