Zotepine

Zotepine is a second‐generation antipsychotic that demonstrates significant efficacy in antagonizing D2 and 5‐HT2A receptors. Although clinical investigations have shown that administering zotepine is associated with an increased prevalence of hyperglycemia and a heightened risk of cardiovascular disease, the side effects of zotepine on voltage‐gated K+ (Kv) channels have not been established. Zotepine suppressed the vascular Kv channels in rabbit coronary arterial smooth muscle cells in a concentration‐dependent manner, with an IC50 of 5.3 ± 0.4 μM and a Hill coefficient of 1.6 ± 0.2. The decay rate of inactivation was significantly accelerated by zotepine. Applying zotepine (10 μM) shifted the steady‐state inactivation curve in a negative direction. Applying train pulses at 1 and 2 Hz resulted in a progressive increase in blockage of the Kv currents by zotepine. Furthermore, zotepine prolonged the recovery time from inactivation. Although pretreatment with the Kv2.1 subtype inhibitor stromatoxin‐1 and the Kv7 subtype inhibitor linopirdine did not change the degree of zotepine‐induced inhibition of Kv currents, pretreatment with the Kv1.5 channel inhibitor DPO‐1 decreased the inhibitory effects of zotepine on Kv currents. Zotepine also induced membrane depolarization. These results indicate that zotepine inhibits Kv currents (mainly Kv1.5 subtype) in dose‐, time‐, and use (state)‐dependent manners by changing the steady‐state inactivation curve.

The G protein‐coupled receptor (GPCR) pharmacology accounts for a significant field in research, clinical studies, and therapeutics. Computer‐aided drug discovery is an evolving suite of techniques and methodologies that facilitate accelerated progress in drug discovery and repositioning. However, the structure–activity relationships of molecules targeting GPCRs are highly challenging in many cases since slight structural modifications can lead to drastic changes in biological functionality. Numerous molecular descriptors have been described, many of which successfully characterize the structural and physicochemical features of drug sets. Nonetheless, elucidating the structure–functionality relationships over extensive sets of drugs with multiple structural variations and known biological activity remains challenging in various biological systems. This work presents novel topological descriptors using Laplacian matrices, weighted, and scaled by atomic mass and partial charges. We tested these descriptors on three sets of GPCR ligands: muscarinic, β‐adrenergic, and δ‐opioid receptor ligands, evaluating their potential as functional descriptors of these receptors.