Author: Fujinaga, Masayuki ; Yu, Qingzhen ; Zhang, Ming-Rong ; Zhang, Yiding ; Chen, Zhen ; Hiraishi, Atsuto ; Rong, Jian ; Xie, Lin ; Zhao, Chunyu ; Ishii, Hideki ; Xiao, Zhiwei ; Tomita, Susumu ; Haider, Achi ; Hu, Kuan ; Yamasaki, Tomoteru ; Chen, Jiahui ; Mori, Wakana ; Collier, Thomas ; Kumata, Katsushi ; Shao, Tuo ; Liang, Steven

The transmembrane α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8) constitutes an auxiliary subunit of AMPA receptors, which mediates various brain functions including learning and memory. TARP γ-8 has emerged as a promising therapeutic target for central nervous system disorders. Despite considerable efforts, previously reported TARP γ-8 PET radioligands, such as [¹¹C]TARP-1903 and [¹¹C]TARP-1811 series, were plagued by limited brain uptake and/or high nonspecific binding in vivo. Herein, we developed two novel ¹¹C-labeled probes, [¹¹C]8 and [¹¹C]15 (also named as [¹¹C]TARP-2105), of which the latter exhibited a reasonable brain uptake as well as specific binding toward TARP γ-8 both in vitro and in vivo, as confirmed by blocking experiments with the commercially available TARP γ-8 inhibitor, JNJ-55511118 in the TARP γ-8-rich hippocampus. Overall, [¹¹C]15 exhibited promising tracer characteristics and proved to be a lead positron-emission tomography ligand for the non-invasive quantification of TARP γ-8 in the mammalian brain.

01 Oct 2020·Journal of Biological ChemistryQ2 · BIOLOGY

Characterizing the binding and function of TARP γ8-selective AMPA receptor modulators

Q2 · BIOLOGY

Article

Author: Greger, Ingo H ; Dohrke, Jan-Niklas ; Birchall, Kristian ; Watson, Jake F

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)-type glutamate receptors (AMPARs) are the predominant excitatory neurotransmitter receptors in the brain, where they mediate synaptic transmission and plasticity. Excessive AMPAR activation leads to diseases such as epilepsy. AMPAR properties are modulated by auxiliary proteins and foremost by the transmembrane AMPAR regulatory proteins (TARPs). These distribute in unique expression patterns across the brain, rendering AMPAR/TARP complexes promising targets for region-specific therapeutic intervention. TARP γ8 is predominantly expressed in the forebrain and is enriched in the hippocampus, a region associated with temporal lobe epilepsy. Recent high-throughput medicinal chemistry screens have identified multiple promising compounds that selectively target AMPARs associated with γ8 and hold promise for epilepsy treatment. However, how these modulators target the receptor complex is currently unknown. Here, we use a combination of ligand docking, molecular dynamics simulations, and electrophysiology to address this question. We identify a conserved oxindole isostere, shared between three structurally diverse modulators (LY-3130481, JNJ-55511118, and JNJ-61432059) as the major module engaging γ8 by an H-bond to Asn-172 (γ8). The remaining variable region of each molecule likely targets the receptor complex in ligand-selective modes. Functional data reveal parallels in the underlying modulatory action of two prominent compounds. This work will aid development of refined AMPAR epilepsy therapeutics and facilitate to uncover the mechanisms by which TARPs modulate the receptor.

14 Mar 2019·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Discovery of Imidazo[1,2-a]pyrazines and Pyrazolo[1,5-c]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators

Q3 · MEDICINE

Article

Author: Lord, Brian ; Wu, Dongpei ; García Olmos, Beatriz ; Koudriakova, Tatiana ; Wu, Nyantsz ; Seierstad, Mark ; Vives Martinez, Jorge ; Lovenberg, Timothy W. ; Ameriks, Michael K. ; Savall, Brad M. ; Maher, Michael P. ; Swanson, Devin M. ; Coe, Kevin ; Carruthers, Nicholas I.

This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as selective negative modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine 5 was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure-activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide 26, JNJ-61432059. Following oral administration, 26 exhibited time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.

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Indication	Highest Phase	Country/Location	Organization	Date
Epilepsy	Discovery	United States	Johnson & Johnson	-

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