First Demonstration of Positive Allosteric-like Modulation at the Human Wild Type Translocator Protein (TSPO)

Rajeshwar Narlawar; Eryn L Werry; Alana M Scarf; Raphy Hanani; Sook Wern Chua; Victoria A King; Melissa L Barron; Ralph N Martins; Lars M Ittner; Louis M Rendina; Michael Kassiou

doi:10.1021/acs.jmedchem.5b01288

First Demonstration of Positive Allosteric-like Modulation at the Human Wild Type Translocator Protein (TSPO)

J Med Chem. 2015 Nov 12;58(21):8743-9. doi: 10.1021/acs.jmedchem.5b01288. Epub 2015 Oct 23.

Authors

Rajeshwar Narlawar, Eryn L Werry, Alana M Scarf, Raphy Hanani, Sook Wern Chua¹, Victoria A King, Melissa L Barron, Ralph N Martins², Lars M Ittner¹, Louis M Rendina, Michael Kassiou

Affiliations

¹ Dementia Research Unit, School of Medical Sciences, University of New South Wales , Sydney, NSW 2052, Australia.
² School of Medical Sciences, Edith Cowan University , Joondalup, WA 6027, Australia.

PMID: 26461041
DOI: 10.1021/acs.jmedchem.5b01288

Abstract

We show that changing the number and position of nitrogen atoms in the heteroatomic core of a pyrazolopyrimidine acetamide is sufficient to induce complex binding to wild type human TSPO. Only compounds with this complex binding profile lacked intrinsic effect on glioblastoma proliferation but positively modulated the antiproliferative effects of a synthetic TSPO ligand. To the best of our knowledge this is the first demonstration of allosteric-like interaction at the wild type human TSPO.

Publication types

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

MeSH terms

Acetamides / chemistry
Acetamides / pharmacology*
Allosteric Regulation / drug effects
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects*
Glioblastoma / drug therapy
Glioblastoma / metabolism
Humans
Protein Binding
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptors, GABA / metabolism*

Substances

Acetamides
Antineoplastic Agents
Pyrimidines
Receptors, GABA
TSPO protein, human