Homochlorcyclizine Hydrochloride

Chinese liquor is obtained from various grains by fermentation and complex processes. Chinese liquor contains complex ingredients. However, the low contents and presence of ethanol restricted the flavor substances function study. In current study, a flavor substance, homofuraneol (HOMO) was isolated from the Chinese liquor and the potency against H2O2‐induced oxidative damage in HepG2 cells and lifespan‐extending ability in Caenorhabditis elegans were explored. Results indicated that HOMO increased the HepG2 cells cytoactive by eliminating excessive intracellular free radicals, upregulating antioxidant enzyme activity and inhibiting the phosphorylation of mitogen‐activated protein kinases (MAPKs) pathway. Further study revealed that HOMO extended the lifespan of N2 nematodes under normal and oxidative stress conditions. Moreover, RT‐PCR results showed that paraquat activated the expression of PMK‐1 and SKN‐1 was significantly regulated by HOMO. Of note, our results indicated that HOMO recovered the redox states of HepG2 cells by targeting MAPKs and upregulating the stress resistance of nematodes by modulating the expression of stress‐responsive genes, such as DAF‐16.

Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels K_v7.1 and Na_v1.8 which triggers an increase in after-hyperpolarization and altered firing properties.

We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (K_V7.1) or HEK293 (Na_v1.8) cells and the HTS used either ⁸⁶Rb⁺ efflux (K_V7.1) or a FLIPR assay (Na_v1.8).

The HTS delivered 55 inhibitors of K_v7.1 (4.2% hit rate) and 93 inhibitors of Na_v1.8 (7.2% hit rate) at a screening concentration of 10 μM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Na_v1.8.

This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Na_v1.8, as there are currently no approved treatments for this rare disorder.