This article, Neuronikinin, was written by RelentlessRecusant. Please do not edit this fiction without the writer's permission.

Neuronikinin, otherwise known as EP-107560 or EZM-3 ("Element Zero Mimetic-3"), is an orally-bioavailable small-molecule chemical compound that serves as a mimetic to element zero in neuronal reprogramming. It was synthesized and characterized by the Alliance Intelligence Service and Ellis Pharmaceuticals under the Paragon Project.

It was initially synthesized as part of a large (~109) structurally-diverse internal collection within Ellis Pharmaceuticals, and this library was screened in a phenotype-based high-throughput screening (HTS) / high-content analysis (HCA) platform in human primary cortical and hippocampal neurons for induction of a morphological phenotype characteristic of element zero reprogramming of neurons. EP-107002 was an initial screening hit, and brief characterization showed that it strongly phenocopied exposure of neurons to femtomolar concentrations of element zero, thus establishing EP-107002, which was henceforth known as psychonikin or EZM-1 ("Element Zero Mimetic-1"), as a promising hit to study neuronal reprogramming by element zero. Subsequent analyses of psychonikin-reprogrammed neurons revealed substantiative morphological, transcriptional, epigenetic, and proteomic changes. It was later determined that the timecourse for reprogramming was on the scale of weeks, and that psychonikin's IC50 = 8 μM. It was resolved that further optimization was necessary to lower the timecourse of psychonikin activity (days) and also its effective concentration (nanomolar) to enable utility in vivo within humans.

Exploration of the structure-activity relationship (SAR) between psychonikin structural analogs and induction of the reprogramming phenotype led to the synthesis of a more potent mimetic, EP-107559, otherwise known as EZM-2 ("Element Zero Mimetic-2"), which had an IC50 = 0.40 nM and which induced the reprogramming phenotype within 96 hours of compound addition to cultured neurons. A third successive round of screening was performed with orally-bioactive lead-like qualities as a terminating goal, culminating in the synthesis of EP-107560, known as neuronikin, and otherwise known as EZM-3 ("Element Zero Mimetic-3").

Neuronikin had an IC50 < 0.20 nM, designating it as a highly potent activator of the reprogramming effect, and was characterized to have proper lead-like properties, showing poor clearance in both human and murine microsome preparations, and showing excellent absorption into immortalized Caco-2 human colorectal cells, predicting neuronikin as an orally-bioavailable compound. This was subsequently confirmed by tracer studies in murine models, and neuronikin (EP-107560) was confirmed as a lead compound, resultant from the original hit-to-lead (HtL) effort by Ellis Pharmaceuticals.

Behind the ScenesEdit

  • Psychonikin and neuronikin are named after robotnikinin, a real-world small-molecule that is a 12-membered macrocycle that is the first characterized specific inhibitor of the sonic hedgehog (Shh) ligand. It was originally described by Stanton et. al. (2009).[1]


  1. Stanton et. al (2009). A small molecule that binds Hedgehog and blocks its signaling in human cells. Nature Chemical Biology (5), 154-156.