First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease.

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.

Eosinophils adhesion assay as a tool for phenotypic drug screening - The pharmacology of 1,3,5 - Triazine and 1H-indole like derivatives against the human histamine H4 receptor.

Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H4 receptor ligands in the treatment of many inflammatory and immunomodulatory diseases, including allergic rhinitis, asthma, atopic dermatitis, colitis or pruritus. Up to date, several potent histamine H4 receptor ligands were developed, none of which was registered as a drug yet. In this study, a series of potent indole-like and triazine derivatives were tested, in radioligand displacement and functional assays at histamine H4 receptor, as well as in human eosinophils adhesion assay to endothelium. For selected compounds permeability, cytotoxicity, metabolic and in vivo studies were conducted. Adhesion assay differentiated the activity of different groups of compounds with a known affinity towards the histamine H4 receptor. Most of the tested compounds downregulated the number of adherent cells. However, adhesion assay revealed additional properties of tested compounds that had not been detected in radioligand displacement and aequorin-based functional assays. Furthermore, for some tested compounds, these abnormal effects were confirmed during the in vivo studies. In conclusion, eosinophils adhesion assay uncovered pharmacological activity of histamine H4 receptor ligands that has been later confirmed in vivo, underscoring the value of well-suited cell-based phenotypic screening approach in drug discovery.

Evaluation of anticonvulsant and analgesic activity of new hybrid compounds derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and -butanamides.

Epilepsy is a chronic neurological disorder that is associated with various types of recurrent seizures, which are drug-resistant in about one third of patients. Moreover, anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic pain. Here, we investigated the anticonvulsant activity of six new hybrid compounds based on the pyrrolidine-2,5-dione scaffold in the 6 Hz corneal stimulation test with 44 mA stimulus intensity in mice, which is the model of pharmacoresistant seizures. We demonstrated that two molecules, DK-10 (11) and DK-14 (14) show higher anticonvulsant activity and similar safety profile in comparison with valproic acid and much higher in comparison with levetiracetam in the aforementioned test. The second aim of this study was to examine analgesic activity of these compounds. For this purpose, the hot plate test, the formalin test, and the oxaliplatin-induced peripheral neuropathy model were performed. Among tested agents DK-11 (12) revealed prominent antinociceptive activity at non-sedative doses in the second (inflammatory) phase of the formalin test, which is the model of tonic pain and antiallodynic activity in the oxaliplatin-induced neuropathic pain, the model of painful chemotherapy-induced peripheral neuropathy. No cytotoxic effect on hepatoma cells was observed. Compound DK-10 (11) had high affinity for voltage-gated sodium channels, whereas compound DK-11 (12) showed weak binding toward sodium and calcium voltage-gated channels and the NMDA receptor. As a result, hybrid compounds reported herein seem to be very promising broad spectrum anticonvulsant molecules with collateral analgesic activity.