Reply to "A Comment on 'Discovery and Characterization of AMPA Receptor Modulators Selective for TARP- 8"

Abstract

Thank you for the opportunity to reply to the comment by Witkin and Gardinier (2016) regarding our recent article, "Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-g8" (Maher et al., 2016). It is scientifically reassuring when two independent lines of research converge to very common conclusions and when distinct chemical entities independently replicate exciting pharmacological findings. We additionally congratulate Drs. Witkin and Gardinier and the entire Eli Lilly team for being the first to publicly disclose an exemplar of this very unique pharmacological class of agents through their patent applications and conference abstracts.We generally prefer to restrict our citations of previous work to the peer-reviewed literature, where we can make reasonable comparisons to those results. Based on the previous disclosures by the Eli Lilly group, we had been anticipating seeing and citing a peer-reviewed publication from them, hence the omission of citations of abstracts and patent applications. However, at the time we wrote our manuscript, submitted it for publication to JPET, and revised the accepted version, none of the work described by Drs. Witkin and Gardinier had yet appeared in a peer-reviewed format. Within a couple of weeks of the publication of our JPET article online, the anticipated manuscript appeared in the Journal of Medicinal Chemistry . We regret that we did not reference the article by members of the Lilly group (Zwart et al., 2014) in our discussion section, as those authors had speculated on the likely benefit of designing an a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptor modulator selective for transmembrane AMPA receptor regulatory protein g8.

Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

“…Recently discovered NAMs target γ8, a TARP strongly enriched in the hippocampus, and show promise in pre-clinical epilepsy studies 31,32 . One example, LY-3130481 (CERC-611), is also effective in the treatment of pain and of gliomas 33,34 , with Phase-2 clinical trials currently ongoing (https:// clinicaltrials.gov/ct2/show/NCT04714996). Understanding the binding modes and allosteric mechanisms of these drugs, will not only facilitate the refinement and development of therapeutics, but also enables unlocking the complexity of TARP modulation of the AMPAR.…”