Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism

Renee Sokias; Eryn L. Werry; Hei Wun Alison Cheng; James H. Lloyd; Greta Sohler; Jonathan J. Danon; Andrew P. Montgomery; Jonathan J. Du; Quanqing Gao; David E. Hibbs; Lars M. Ittner; Tristan A. Reekie; Michael Kassiou

doi:10.1016/j.ejmech.2020.112725

Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism

Renee Sokias, Eryn L. Werry, Hei Wun Alison Cheng, James H. Lloyd, Greta Sohler, Jonathan J. Danon, Andrew P. Montgomery, Jonathan J. Du, Quanqing Gao, David E. Hibbs, Lars M. Ittner, Tristan A. Reekie, Michael Kassiou^*

^*Corresponding author for this work

Faculty of Medicine, Health and Human Sciences

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

The 18 kDa translocator protein (TSPO) is a target for the development of imaging agents to detect neuroinflammation. The clinical utility of second-generation TSPO ligands has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Given the complex nature of TSPO binding, and the lack of non-discriminating high-affinity ligands at both wild type and A147T forms of TSPO, a series of novel TSPO ligands containing various heterocyclic scaffolds was developed to explore the pharmacophoric drivers of affinity loss at TSPO A147T. In general, N-benzyl-N-methyl-substituted amide ligands showed increased affinity at TSPO A147T, and a pyrazolopyrimidine acetamide containing this motif displayed low nanomolar binding affinities to both TSPO forms.

Original language	English
Article number	112725
Pages (from-to)	1-12
Number of pages	12
Journal	European Journal of Medicinal Chemistry
Volume	207
Early online date	15 Aug 2020
DOIs	https://doi.org/10.1016/j.ejmech.2020.112725
Publication status	Published - 1 Dec 2020

Keywords

Docking
Microglia
Non-discriminating
Polymorphism
Structure-activity relationships
TSPO

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10.1016/j.ejmech.2020.112725

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Sokias, R., Werry, E. L., Alison Cheng, H. W., Lloyd, J. H., Sohler, G., Danon, J. J., Montgomery, A. P., Du, J. J., Gao, Q., Hibbs, D. E., Ittner, L. M., Reekie, T. A., & Kassiou, M. (2020). Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism. European Journal of Medicinal Chemistry, 207, 1-12. Article 112725. https://doi.org/10.1016/j.ejmech.2020.112725

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title = "Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism",

abstract = "The 18 kDa translocator protein (TSPO) is a target for the development of imaging agents to detect neuroinflammation. The clinical utility of second-generation TSPO ligands has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Given the complex nature of TSPO binding, and the lack of non-discriminating high-affinity ligands at both wild type and A147T forms of TSPO, a series of novel TSPO ligands containing various heterocyclic scaffolds was developed to explore the pharmacophoric drivers of affinity loss at TSPO A147T. In general, N-benzyl-N-methyl-substituted amide ligands showed increased affinity at TSPO A147T, and a pyrazolopyrimidine acetamide containing this motif displayed low nanomolar binding affinities to both TSPO forms.",

keywords = "Docking, Microglia, Non-discriminating, Polymorphism, Structure-activity relationships, TSPO",

author = "Renee Sokias and Werry, {Eryn L.} and {Alison Cheng}, {Hei Wun} and Lloyd, {James H.} and Greta Sohler and Danon, {Jonathan J.} and Montgomery, {Andrew P.} and Du, {Jonathan J.} and Quanqing Gao and Hibbs, {David E.} and Ittner, {Lars M.} and Reekie, {Tristan A.} and Michael Kassiou",

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doi = "10.1016/j.ejmech.2020.112725",

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AU - Sokias, Renee

AU - Werry, Eryn L.

AU - Alison Cheng, Hei Wun

AU - Lloyd, James H.

AU - Sohler, Greta

AU - Danon, Jonathan J.

AU - Montgomery, Andrew P.

AU - Du, Jonathan J.

AU - Gao, Quanqing

AU - Hibbs, David E.

AU - Ittner, Lars M.

AU - Reekie, Tristan A.

AU - Kassiou, Michael

PY - 2020/12/1

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N2 - The 18 kDa translocator protein (TSPO) is a target for the development of imaging agents to detect neuroinflammation. The clinical utility of second-generation TSPO ligands has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Given the complex nature of TSPO binding, and the lack of non-discriminating high-affinity ligands at both wild type and A147T forms of TSPO, a series of novel TSPO ligands containing various heterocyclic scaffolds was developed to explore the pharmacophoric drivers of affinity loss at TSPO A147T. In general, N-benzyl-N-methyl-substituted amide ligands showed increased affinity at TSPO A147T, and a pyrazolopyrimidine acetamide containing this motif displayed low nanomolar binding affinities to both TSPO forms.

AB - The 18 kDa translocator protein (TSPO) is a target for the development of imaging agents to detect neuroinflammation. The clinical utility of second-generation TSPO ligands has been hindered by the presence of a polymorphism, rs6971, which causes a non-conservative substitution of alanine for threonine at amino acid residue 147 (TSPO A147T). Given the complex nature of TSPO binding, and the lack of non-discriminating high-affinity ligands at both wild type and A147T forms of TSPO, a series of novel TSPO ligands containing various heterocyclic scaffolds was developed to explore the pharmacophoric drivers of affinity loss at TSPO A147T. In general, N-benzyl-N-methyl-substituted amide ligands showed increased affinity at TSPO A147T, and a pyrazolopyrimidine acetamide containing this motif displayed low nanomolar binding affinities to both TSPO forms.

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KW - Microglia

KW - Non-discriminating

KW - Polymorphism

KW - Structure-activity relationships

KW - TSPO

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UR - http://purl.org/au-research/grants/nhmrc/1132524

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JO - European Journal of Medicinal Chemistry

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ER -

Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism

Abstract

Keywords

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