Neuromuscular blocking agents (NMBAs) are routinely used during anesthesia to relax skeletal muscle. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels; NMBAs can induce muscle paralysis by preventing the neurotransmitter acetylcholine (ACh) from binding to nAChRs situated on the postsynaptic membranes. Despite widespread efforts, it is still a great challenge to find new NMBAs since the introduction of cisatracurium in 1995. In this work, an effective ensemble-based virtual screening method, including molecular property filters, 3D pharmacophore model, and molecular docking, was applied to discover potential NMBAs from the ZINC15 database. The results showed that screened hit compounds had better docking scores than the reference compound d-tubocurarine. In order to further investigate the binding modes between the hit compounds and nAChRs at simulated physiological conditions, the molecular dynamics simulation was performed. Deep analysis of the simulation results revealed that ZINC257459695 can stably bind to nAChRs’ active sites and interact with the key residue Asp165. The binding free energies were also calculated for the obtained hits using the MM/GBSA method. In silico ADMET calculations were performed to assess the pharmacokinetic properties of hit compounds in the human body. Overall, the identified ZINC257459695 may be a promising lead compound for developing new NMBAs as an adjunct to general anesthesia, necessitating further investigations.

Background: Propofol is used worldwide as a short-acting intravenous anesthetic in clinical practice; however, side effects such as injection pain and respiratory depression remain clinically relevant. Therefore, identification of safer propofol analogs is required. Method: In response to the urgent need for optimized potency and reduced side effects, a series of dihydrobenzofuran derivatives were designed as expectedly better propofol analogs through conformational restriction. A loss of righting reflex assay was conducted to evaluate the sedative/anesthetic properties of the synthesized compounds, and a respiratory depression test was performed for safety assessment. Results: Most of the designed compounds were shown to possess promising anesthetic properties as propofol analogs. The represented 53A had higher potency and a wider safety margin (ED₅₀:3.898 vs. 8.040 mg/kg in mice; 2.985 vs. 5.894 mg/kg in rats; TI (therapeutic index): 6.172 vs. 5.061 in mice; 4.362 vs. 2.580 in rats) than propofol, and fast onset and recovery times were maintained. The phosphate prodrug 56A also exhibited better efficiency and safety than fospropofol, along with a longer duration and faster recovery time in sedative profiles. Furthermore, alleviation of the adverse effects of respiratory depression has been demonstrated. Conclusions: 53A has the potential to be selected as a preclinical candidate for clinical development.

Background: Schizophrenia is a serious psychiatric disorder that significantly affects the quality of life of patients. The objective of this study is to discover a novel antipsychotic candidate with highly antagonistic activity against both serotonin and dopamine receptors, demonstrating robust efficacy in animal models of positive, negative, and cognitive symptoms of schizophrenia.Methods: In the present study, we examined the activity of antipsychotic drug (NH300094) on 5-HT_2A, 5-HT_2C, 5-HT_1A, 5-HT_1B, 5-HT₇, H₁, M₁, Alpha_1A, D_2L, D_2S, Alpha_2A, D₃ receptor functional assay in vitro. In addition, multiple animal models, including dizocilpine (MK-801) induced hyper-locomotion; APO induced climbing; Conditioned Avoidance Response (CAR); DOI-Induced Head Twitch; Forced swimming test; Scopolamine induced cognitive impairment model, were used to verify the antipsychotic activity of NH300094 in preclinical.Results:In vitro functional assays have indicated that NH300094 is a potent antagonist of 5-HT receptors and dopamine receptors, with higher relative antagonistic activity against 5-HT_2A receptor (5-HT_2A IC₅₀ = 0.47 nM) than dopamine receptors (D_2L IC₅₀ = 1.04 nM; D_2S IC₅₀ = 11.71 nM; D₃ IC₅₀ = 31.55 nM). Preclinical in vivo pharmacological study results showed that NH300094 was effective in multiple models, which is more extensive than the clinic drug Risperidone. Furthermore, the safety window for extrapyramidal side effects of NH300094 is significantly wider than that of Risperidone (For NH300094, mice catalepsy model ED₅₀/ Mice MK-801 model ED₅₀ = 104.6-fold; for Risperidone, mice catalepsy model ED₅₀/ Mice MK-801 model ED₅₀ = 12.9-fold), which suggests a potentially better clinical safety profile for NH300094.Conclusion: NH300094 is a novel potent serotonin and dopamine receptors modulator, which has good safety profile and therapeutic potential for the treatment of schizophrenia with cognition disorders.