1. Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8
- Author
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Hong Yu, Sean P. Hollinshead, Anne B. Need, Akihiko Kato, Daniel Ray Mayhugh, Diseroad Benjamin Alan, Paul L. Ornstein, Jon K. Reel, Patrick Gianpietro Spinazze, Jeff Schkeryantz, David S. Bredt, Oscar de Frutos, Beverly A. Heinz, Kevin Matthew Gardinier, Debra Luffer-Atlas, F. Craig Stevens, Vanessa N. Barth, Warren J. Porter, Timothy Andrew Woods, Douglas Linn Gernert, Gregory A. Stephenson, Jeffrey M. Witkin, Kevin D. Burris, Prashant V. Desai, Patric James Hahn, Scott D. Gleason, Steven Swanson, Chunjin Ding, and Albert Khilevich
- Subjects
0301 basic medicine ,Scaffold protein ,Molecular Structure ,Chemistry ,Drug discovery ,Antagonist ,Hippocampus ,AMPA receptor ,Pharmacology ,Transmembrane protein ,High-Throughput Screening Assays ,Molecular Docking Simulation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,nervous system ,In vivo ,Drug Discovery ,Molecular Medicine ,Humans ,Calcium Channels ,Receptors, AMPA ,Receptor ,030217 neurology & neurosurgery - Abstract
Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.
- Published
- 2016