Paul Ornstein - 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.

Document created by Paul Ornstein on Jan 17, 2017
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  Gardinier, Kevin M, Gernert, Douglas L, Porter, Warren J, Reel,   Jon K, Ornstein, Paul L, Spinazze, Patrick, Stevens, F Craig,   Hahn, Patric, Hollinshead, Sean P, Mayhugh, Daniel, Schkeryantz,   Jeff, Khilevich, Albert, De Frutos, Oscar, Gleason, Scott D,   Kato, Akihiko S, Luffer-Atlas, Debra, Desai, Prashant V, Swanson,   Steven, Burris, Kevin D, Ding, Chunjin, Heinz, Beverly A, Need,   Anne B, Barth, Vanessa N, Stephenson, Gregory A, Diseroad,   Benjamin A, Woods, Tim A, Yu, Hong, Bredt, David, Witkin, Jeffrey   M Journal Of Medicinal Chemistry 2016  59 (10) 4753-4768

  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.;

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