In Vitro screening for seizure liability using microelectrode array technology was written by Bradley, Jenifer A.;Luithardt, Harry H.;Metea, Monica R.;Strock, Christopher J.. And the article was included in Toxicological Sciences in 2018.Quality Control of Thioridazine hydrochloride This article mentions the following:
Drug-induced seizure liabilities produce significant compound attrition during drug discovery. Currently available in vitro cytotoxicity assays cannot predict all toxicity mechanisms due to the failure of these assays to predict sublethal target-specific electrophysiol. liabilities. Identification of seizurogenic and other electrophysiol. effects at early stages of the drug development process is important to ensure that safe candidate compounds can be developed while chem. is taking place, long before these liabilities are discovered in costly preclin. in vivo studies. The development of a high throughput and reliable in vitro assay to screen compounds for seizure liabilities would de-risk compounds significantly earlier in the drug discovery process and with greater dependability. Here the authors describe a method for screening compounds that utilizes rat cortical neurons plated onto multiwell microelectrode array plates to identify compounds that cause neurophysiol. disruptions. Changes in 12 electrophysiol. parameters (spike train descriptors) were measured after application of known seizurogenic compounds and the response pattern was mapped relative to neg. controls, vehicle control and neurotoxic controls. Twenty chems. with a variety of therapeutic indications and targets, including GABAA antagonists, glycine receptor antagonists, ion channel blockers, muscarinic agonist, 未-opioid receptor agonist, dopaminergic D2/adrenergic receptor blocker and nonsteroidal anti-inflammatory drugs, were tested to assess this system. Sixteen of the seventeen seizurogenic/neurotoxic compounds tested pos. for seizure liability or neurotoxicity, moreover, different endpoint response patterns for firing rate, burst characteristics and synchrony that distinguished the chems. into groups relating to target and seizurogenic response emerged from the data. The neg. and vehicle control compounds had no effect on neural activity. In conclusion, the multiwell microelectrode array platform using cryopreserved rat cortical neurons is a highly effective high throughput method for reliably screening seizure liabilities within an early de-risking drug development paradigm. In the experiment, the researchers used many compounds, for example, Thioridazine hydrochloride (cas: 130-61-0Quality Control of Thioridazine hydrochloride).
Thioridazine hydrochloride (cas: 130-61-0) belongs to piperidine derivatives. Piperidine is a metabolite of cadaverine, a polyamine found in the human intestine. Fluorinated piperidines are also the subject of continued interest in medicinal chemistry, for example in the synthesis of selective dipeptidyl peptidase II (DPP II) inhibitors. Piperidine derivatives are also used in solid-phase peptide synthesis (SPPS) and many degradation reactions.Quality Control of Thioridazine hydrochloride
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem