First Nondiscriminating Translocator Protein Ligands Produced from a Carbazole Scaffold

Hei Wun Alison Cheng; Renee Sokias; Eryn L Werry; Lars M Ittner; Tristan A Reekie; Jonathan Du; Quanqing Gao; David E Hibbs; Michael Kassiou

doi:10.1021/acs.jmedchem.9b00980

First Nondiscriminating Translocator Protein Ligands Produced from a Carbazole Scaffold

J Med Chem. 2019 Sep 12;62(17):8235-8248. doi: 10.1021/acs.jmedchem.9b00980. Epub 2019 Aug 28.

Authors

Hei Wun Alison Cheng, Renee Sokias, Eryn L Werry, Lars M Ittner¹, Tristan A Reekie, Jonathan Du, Quanqing Gao, David E Hibbs, Michael Kassiou

Affiliation

¹ Department of Biomedical Sciences, Faculty of Medicine and Health Sciences , Macquarie University , 2 Technology Place , North Ryde , New South Wales 2109 , Australia.

PMID: 31419132
DOI: 10.1021/acs.jmedchem.9b00980

Abstract

Development of neuroinflammation agents targeting the translocator protein (TSPO) has been hindered by a common single nucleotide polymorphism (A147T) at which TSPO ligands commonly lose affinity. To this end, carbazole acetamide scaffolds were synthesized and structure activity relationships elaborated to explore the requirements for high-affinity binding to both TSPO wild type (WT) and the polymorphic TSPO A147T. This study reports high binding affinity and nondiscriminating TSPO ligands.

Publication types

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

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Carbazoles / chemical synthesis
Carbazoles / chemistry
Carbazoles / pharmacology*
Dose-Response Relationship, Drug
Humans
Ligands
Molecular Structure
Polymorphism, Single Nucleotide / drug effects
Polymorphism, Single Nucleotide / genetics
Receptors, GABA / genetics
Receptors, GABA / metabolism*
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
Carbazoles
Ligands
Receptors, GABA
TSPO protein, human
carbazole