1521-0103/358/3/502–503$25.00 http://dx.doi.org/10.1124/jpet.116.234419 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 358:502–503, September 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics A Comment on “Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-g8” Jeffrey M. Witkin and Kevin M. Gardinier Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana Received April 12, 2016; accepted May 26, 2016 We would like to make the readers of JPET aware of literature precedents for the very exciting work recently published by Maher et al. (2016) (“Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-g8”) in JPET. In this article, Maher et al. (2016) describe a molecule that selec- tively blocks a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptors associated with the auxiliary protein transmembrane AMPA receptor regulatory protein (TARP)- g8. Given the unique localizations of these AMPA receptors in the brain, the molecule was anticonvulsant and had fewer motor-impacting effects than non-TARP–dependent AMPA receptor antagonists. For example, the antiepileptic peram- panel (Fycompa; Eisai Inc., Woodcliff Lake, NJ) produces motor-impairing effects in rodents and humans (see data and discussion in Zwart et al., 2014). We believe the clinical impli- cations of these new data are therefore important. We note be- low that multiple disclosures in 2014 and 2015 had already documented structurally unique molecules along these lines. First, our research team published patents on molecules with this mechanism of action in 2014 and 2015, which documented their unique anticonvulsant and non–motor-impairing effects (see Reel and Porter, 2014; Gardinier et al., 2015a). We have also disclosed the screening methods, chemistry, and biologic data on our TARP- g8–selective molecule with anticon- vulsant activity, LY3130481 [(6-((S)-1-{1-[5-(2-hydroxy-ethoxy)- pyridin-2-yl]-1H-pyrazol-3-yl}-ethyl)-3H-1,3-benzothiazol-2-one] in multiple venues, including the 2015 Neurologic Disorders Sum- mit (Witkin et al., 2015b), the 2015 American Chemical Society National Meeting (Gardinier et al., 2015b), and the 2015 Society for Neuroscience Annual Meeting (Ding et al., 2015; Gernert et al., 2015; Kato et al., 2015; Knopp et al., 2015; Witkin et al., 2015a). We also point out that an article published in JPET in 2014 predicted the data presented by Maher et al. (Zwart et al., 2014). In the abstract, we stated that “These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side effect profile in rodents and epileptic patients.” The discus- sion section then makes this prediction explicit: “Thus, an AMPA receptor antagonist that has reduced potency and/or efficacy at AMPA receptors associated with TARP-g2 rela- tive to other AMPA receptor isoforms might provide anti- epileptic control without the cerebellar-mediated motor side effects.” References Ding C, Heinz B, Kato AS, Yu H, Gardinier KM, Gernert DL, Bredt DS, Witkin JM, and Burris KD (2015) An assay system for the detection of transmembrane AMPA receptor regulatory protein (TARP) g-8 selective antagonists: in vitro characterization of LY3130481, in Proceedings of Neuroscience 2015; 2015 Oct 17–21; Chicago. Society for Neuroscience, Washington, DC. Gardinier KM, Gernert DL, Hahn PJ, Hollinshead SP, Khilevich A, Mayhugh DR, Ornstein PL, Porter WJ, Reel JK, Schkeryantz JM, et al. (2015a) inven- tors, Eli Lilly and Company, assignee. 6-Substituted-3H-1,3-benzothiazol-2- one compounds as TARP-gamma 8 dependent AMPA receptor antagonists U.S. patent US20150344468 A1. 2015 Dec 3. Gardinier KM, Porter W, Gernert D, Swanson S, Desai P, Ding C, Burris K, Ornstein P, and Reel J (2015b) Discovery of a TARP-g-8 dependent AMPA receptor antag- onist (TDAA) for the treatment of epilepsy, in Proceedings of the 2015 American Chemical Society National Meeting and Exposition; 2015 Aug 16–20; Boston. American Chemical Society, Washington, DC. Gernert D, Gardinier K, Witkin J, Porter WJ, Reel J, Spinazze P, Stevens FC, Hahn P, Ornstein P, Hollinshead S, et al. (2015) Discovery of a selective TARP- g8 dependent AMPA receptor antagonist (TDAA), in Proceedings of Neuro- science 2015; 2015 Oct 17–21; Chicago. Society for Neuroscience, Washington, DC. Kato AS, Ding C, Gardinier KM, Gernert DL, Yu H, Zwart R, Wang H, Qian Y, Pasqui F, Sher E, et al. (2015) Discovery of a forebrain-specific AMPA receptor antagonist: electrophysiological characterization of a TARP-g8-dependent AMPA receptor antagonist, in Proceedings of Neuroscience 2015; 2015 Oct 17–21; Chicago. Society for Neuroscience, Washington, DC. Knopp KL, Simmons RMA, Guo W, Adams BL, Witkin JM, Gardinier KM, Gernert DL, Ornstein P, Porter W, Reel J, et al. (2015) TARP-g8 dependent AMPA receptor antagonists as a novel therapeutic approach for chronic pain, in Proceedings of Neuroscience 2015; 2015 Oct 17–21; Chicago. Society for Neuroscience, Wash- ington, DC. Maher MP, Wu N, Ravula S, Ameriks MK, Savall BM, Liu C, Lord B, Wyatt RM, Matta JA, Dugovic C, et al. (2016) Discovery and characterization of AMPA receptor modulators selective for TARP-g8. J Pharmacol Exp Ther 357: 394–414. Reel JK and Porter WJ (2014b) inventors, Eli Lilly and Company, assignee. 6-((S)-1-{1-[5- (2-hydroxy-ethoxy)-pyridin-2-yl]-1H-pyrazol-3-YL}-ethyl)-3H-1,3-benzothiazol-2-one as a TARP-gamma 8 dependent AMPA receptor antagonist. U.S. patent US8765960 B2. 2014 Jul 1. Witkin JM, Kato A, Gleason SD, Gernert D, Ornstein P, Porter W, Reel J, and Gardinier KM (2015a) Anticonvulsant and improved side-effect potential of LY3130481: the first g8-selective transmembrane AMPA receptor regulatory This Letter to the Editor is in response to “Discovery and characterization of AMPA receptor modulators selective for TARP-g8” by Maher MP, Wu N, Ravula S, Ameriks MK, Savall BM, Liu C, Lord B, Wyatt RM, Matta JA, Dugovic C, et al., found in J Pharmacol Exp Ther 2016, 357:394–414. dx.doi.org/10.1124/jpet.116.234419. ABBREVIATIONS: AMPA, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid; LY3130481, (6-((S)-1-{1-[5-(2-hydroxy-ethoxy)-pyridin-2-yl]- 1H-pyrazol-3-yl}-ethyl)-3H-1,3-benzothiazol-2-one; TARP, transmembrane AMPA receptor regulatory protein. 502 at ASPET Journals on May 26, 2020 jpet.aspetjournals.org Downloaded from