Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HT6R ligands with noticeable action on AChE/BChE and chalcogen-dependent intrinsic activity in search for new class of drugs against Alzheimer's disease

Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (Ki < 200 nM) and selectivity towards 5-HT6R, with respect to 5-HT2AR, 5-HT7R, and D2R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives

Characteristic of lviv's hippie community

Praca dotyczy charakterystyki hipisowskiej kontrkultury, jej lwowskiego odłamu. Do pracy załączone zostały wywiady z przedstawicielami kontrkultury. Innym źródłem były wspomnienia i eseje hipisów zawarte przede wszystkim w almanachu "Hippi u Lwowi". Za pomocą tych źródeł starałam się przedstawić główne idee ruchu hipisowskiego , oraz ich postrzeganie przez przedstawicieli ruchu we Lwowie.The work concerns the characteristics of the hippie counter-culture, the Lviv faction. To work were attached interviews with representatives of counterculture. Another source were memories and essays written by hippies contained primarily in the almanac "Hippi in Lviv." Using these sources, I tried to present the main ideas of the hippie movement, and their perception by the representatives of the movement in Lviv

Selective 5-HT6 receptor ligands (Agonist and Antagonist) show different effects on antipsychotic drug-induced metabolic dysfunctions in rats

It is estimated that in patients taking antipsychotic drugs (APDs), metabolic syndrome occurs 2–3 times more often than in the general population. It manifests itself in abdominal obesity, elevated glucose concentration, and dyslipidemia. Despite the high prevalence of this disorder, only a small percentage of patients receive appropriate and effective treatment, and none of the available methods for preventing or treating APD-induced metabolic side effects is satisfactory. A promising supplement to antipsychotic therapy appears to be ligands of the serotonin 6 (5-HT6) receptor. The present study aimed to examine the chronic effects of the selected APDs (haloperidol, risperidone, olanzapine), administered alone and in combination with a selective 5-HT6 agonist (WAY-181187) or antagonist (SB-742457), on weight gain, food intake, serum lipid profile, glucose level, and a spectrum of hormones derived from adipose (leptin, adiponectin) and gastrointestinal (insulin, ghrelin) tissue in rats. SB-742457 inhibited increased weight gain and alleviated hyperglycemia induced by APDs more strongly than did WAY-181187, but also intensified dyslipidemia. WAY-181187 tended to improve the lipid profile, but increased the glucose level. The greatest benefits were obtained when WAY-181187 or SB-742457 were co-administered with haloperidol. It is difficult to assess whether the modification of the serum levels of insulin, leptin, ghrelin, and adiponectin depended on the treatment applied or other drug-independent factors; therefore, further research is needed