**Background**
The sigma-1 receptor ($\sigma_1$R) is a unique chaperone protein located primarily at the mitochondria-associated endoplasmic reticulum membrane (MAM). It plays a critical role in modulating calcium signaling, protein folding, and cellular stress responses. Due to its widespread expression in the central and peripheral nervous systems, $\sigma_1$R has become a significant target for treating various neurological and respiratory disorders. Specifically, agonists of this receptor are often explored for their potential to modulate cough reflexes and smooth muscle tone. In the context of respiratory health, agents that can inhibit bronchial interceptors and reduce airway resistance are of high therapeutic value. Therefore, we will introduce a potent sigma-1 receptor agonist – Pentoxyverine.
**Definition**
Pentoxyverine (also known as Carbetapentane) is an orally active sigma-1 receptor agonist and muscarinic antagonist. According to the Pentoxyverine technical information, it exhibits $K_i$ values of 41 nM for $\sigma_1$, 894 nM for $\sigma_2$, and 75 nM for guinea-pig brain membrane $\sigma_1$.
**In Vitro and In Vivo Studies**
The Pentoxyverine description highlights its utility as a potent antitussive, anticonvulsant, and spasmolytic agent. In vitro studies have demonstrated its antiproliferative activity; specifically, Pentoxyverine in vitro assays showed an $EC_{50}$ of 28.16 $\mu$M against mouse astrocyte cells and 2.083 $\mu$M against mouse medulloblastoma cells harboring heterozygous ptch1 genes, both measured by MTT assay. Additionally, it inhibits human OCT1 expressed in HEK293 cells with an $IC_{50}$ of 1.55 $\mu$M.
Regarding Pentoxyverine In Vivo activity, the compound has been extensively tested in mouse models. In female wild-type mice (25-30 g), subcutaneous administration of Pentoxyverine (0.5, 1, 2, 4, 8, 16, 32 mg/kg) 30 minutes prior to intraplantar capsaicin administration dose-dependently potentiated the sensitizing effect of capsaicin to mechanical stimuli. Notably, a dose of 16 mg/kg showed strong potentiation of capsaicin-induced secondary mechanical allodynia. Furthermore, when used as a positive control at 50 mg/kg orally for 7 days, Pentoxyverine increased the latent period of aqueous ammonia-induced cough by 121.72% and inhibited cough frequency by 45.45%. In conclusion, Pentoxyverine is a versatile $\sigma_1$ receptor agonist with significant applications in respiratory and nociceptive research.
Keywords
Pentoxyverine, 77-23-6, Carbetapentane, Sigma Receptor, mAChR, Muscarinic acetylcholine receptor, sigma-1 receptor, σ1, σ2, muscarinic, antitussive, anticonvulsant, spasmolytic, bronchial interceptor, cough reflex
References
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