Search Results (3)

Background/Objectives: The novel pyrazoloquinolinone ligand CW-02-79 shows a unique profile of selective binding to σ2 receptors, but its poor solubility in both water and lipids makes its research and development a burdensome task. We aimed to develop a phospholipid-complex-based nanoemulsion formulation containing CW-02-79 suitable for intravenous administration in preclinical research. Methods: The decorated and undecorated nanoemulsions were formulated and subjected to detailed physiochemical characterization. The delivery and exposure to CW-02-79 from selected nanoemulsions were examined in the in vitro blood–brain barrier model based on human-induced pluripotent stem-cell-derived microvascular endothelial cells, astrocytes, and pericytes, and in vivo neuropharmacokinetic study in rats, respectively. Results: The developed biocompatible nanoemulsions loaded with a CW-02-79—phospholipid complex at a mass ratio of 1:10 exhibited a small droplet size and narrow size distribution, with satisfactory physicochemical stability during steam sterilization and short-term storage at 25 °C. The analysis of protein binding interactions revealed that the PEGylated nanoemulsions had fewer observable interactions compared to the undecorated nanoemulsions, especially when 0.2% DSPE-PEG2000 and 0.1% DSPE-PEG2000-mannose were combined. An in vitro BBB study demonstrated that a substantial part of CW-02-79 present in the applied nanoemulsion is able to permeate the barrier. The quantification of CW-02-79 in plasma/brain homogenate and calculated pharmacokinetic parameters confirmed good systemic and brain availability after intravenous administration. There were subtle differences in the pharmacokinetic parameters in favor of a dual surface-functionalized nanoemulson containing the glucose transporter-1-targeting ligand (mannose). Conclusions: The developed and characterized nanoemulsions enable substantial brain exposure to CW-02-79 as a prerequisite for a pharmacologically and clinically relevant selective modulation of σ2 receptors. Full article

Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain. Full article

Many allosteric binding sites that modulate gamma aminobutyric acid (GABA) effects have been described in heteropentameric GABA type A (GABA_A) receptors, among them sites for benzodiazepines, pyrazoloquinolinones and etomidate. Diazepam not only binds at the high affinity extracellular “canonical” site, but also at sites in the transmembrane domain. Many ligands of the benzodiazepine binding site interact also with homologous sites in the extracellular domain, among them the pyrazoloquinolinones that exert modulation at extracellular α+/β− sites. Additional interaction of this chemotype with the sites for etomidate has also been described. We have recently described a new indole-based scaffold with pharmacophore features highly similar to pyrazoloquinolinones as a novel class of GABA_A receptor modulators. Contrary to what the pharmacophore overlap suggests, the ligand presented here behaves very differently from the identically substituted pyrazoloquinolinone. Structural evidence demonstrates that small changes in pharmacophore features can induce radical changes in ligand binding properties. Analysis of published data reveals that many chemotypes display a strong tendency to interact promiscuously with binding sites in the transmembrane domain and others in the extracellular domain of the same receptor. Further structural investigations of this phenomenon should enable a more targeted path to less promiscuous ligands, potentially reducing side effect liabilities. Full article