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

ABSTRACT: This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as selective negative modulators of ?-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein ?-8. Imidazopyrazine 5 was initially identified as a promising ?-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/?-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.

SUBMITTER: Savall BM

PROVIDER: S-EPMC6421542 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Savall Brad M BM Wu Dongpei D Swanson Devin M DM Seierstad Mark M Wu Nyantsz N Vives Martinez Jorge J García Olmos Beatriz B Lord Brian B Coe Kevin K Koudriakova Tatiana T Lovenberg Timothy W TW Carruthers Nicholas I NI Maher Michael P MP Ameriks Michael K MK

ACS medicinal chemistry letters 20181226 3

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 ...[more]

PMID: 30891124

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Project description:The number of AMPA-type glutamate receptors (AMPARs) at synapses is the major determinant of synaptic strength and varies from synapse to synapse. To clarify the underlying molecular mechanisms, the density of AMPARs, PSD-95, and transmembrane AMPAR regulatory proteins (TARPs) were compared at Schaffer collateral/commissural (SCC) synapses in the adult mouse hippocampal CA1 by quantitative immunogold electron microscopy using serial sections. We examined four types of SCC synapses: perforated and nonperforated synapses on pyramidal cells and axodendritic synapses on parvalbumin-positive (PV synapse) and pravalbumin-negative interneurons (non-PV synapse). SCC synapses were categorized into those expressing high-density (perforated and PV synapses) or low-density (nonperforated and non-PV synapses) AMPARs. Although the density of PSD-95 labeling was fairly constant, the density and composition of TARP isoforms was highly variable depending on the synapse type. Of the three TARPs expressed in hippocampal neurons, the disparity in TARP γ-2 labeling was closely related to that of AMPAR labeling. Importantly, AMPAR density was significantly reduced at perforated and PV synapses in TARP γ-2-knock-out (KO) mice, resulting in a virtual loss of AMPAR disparity among SCC synapses. In comparison, TARP γ-8 was the only TARP expressed at nonperforated synapses, where AMPAR labeling further decreased to a background level in TARP γ-8-KO mice. These results show that synaptic inclusion of TARP γ-2 potently increases AMPAR expression and transforms low-density synapses into high-density ones, whereas TARP γ-8 is essential for low-density or basal expression of AMPARs at nonperforated synapses. Therefore, these TARPs are critically involved in AMPAR density control at SCC synapses.Significance statementAlthough converging evidence implicates the importance of transmembrane AMPA-type glutamate receptor (AMPAR) regulatory proteins (TARPs) in AMPAR stabilization during basal transmission and synaptic plasticity, how they control large disparities in AMPAR numbers or densities across central synapses remains largely unknown. We compared the density of AMPARs with that of TARPs among four types of Schaffer collateral/commissural (SCC) hippocampal synapses in wild-type and TARP-knock-out mice. We show that the density of AMPARs correlates with that of TARP γ-2 across SCC synapses and its high expression is linked to high-density AMPAR expression at perforated type of pyramidal cell synapses and synapses on parvalbumin-positive interneurons. In comparison, TARP γ-8 is the only TARP expressed at nonperforated type of pyramidal cell synapses, playing an essential role in low-density or basal AMPAR expression.

Dataset Information

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

Publications

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

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