Evaluation of antiplatelet activity of novel guanidine derivatives in the aspects of their adrenergic receptor activity

Designed acetamide derivatives based on guanidine and various heteroaryl carboxylic acids, were preliminary in vitro study of their adrenergic receptor affinity and anti-plateled effects. The obtained results have showed that exchange of 2,6-dichloro-phenyl substituent of guanidine into heteroaryl moieties, caused the decrease of receptor affinity, especially for α1-adrenoceptors. The observed receptor profile of activity for α2BAR was not changed compared to α1-ARs. Moreover, the observed effects on platelet aggregation induced by sub-threshold concentration of collagen and adrenaline strongly suggested that antiaggregant effect of N- (diaminomethylene)-2-(pyridin-3-yl)acetamide and N-(diaminomethylene)-2-(pyridin-4-yl)acetamide depends on their α2B-ARs antagonistic activity

Aryl-1,3,5-triazine ligands of histamine H4H_{4} receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide

Objective and design Histamine $H_{4}$ receptor ($H_{4}R$) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of $H_{4}R$ with particular reference to their anti-inflammatory and analgesic activity. Materials and subjects We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test. Treatments In the in vivo tests, animals were pre-treated with the increasing doses of investigated compounds (12.5, 25 and 50 mg/kg) and reference compounds: JNJ7777120 (25 mg/kg), indomethacin (10 mg/kg). Macrophages were pre-treated with two concentrations of tested compounds 100 and 10 $\mu$M. Methods We examined anti-inflammatory and analgesic effects of the new $H_{4}R$ antagonists in the in vivo models of inflammation induced by carrageenan or zymosan. We assessed the level of cAMP and release of cytokines, ROS and NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Moreover, we assessed the affinity of the investigated compounds for histamine $H_{1}$ receptor in functional studies. Results Both investigated compounds reduced paw edema, mechanical and thermal hyperalgesia in the carrageenaninduced acute inflammation. Moreover, administration of the investigated compounds resulted in decreased granulocyte influx and attenuated nociceptive reaction in the zymosan-induced peritonitis model. In the same model of inflammation, the investigated compounds reduced vascular permeability; however, this effect was observed only after the highest applied dose. Furthermore, the test compounds had no impact on cell viability in the experiments on RAW 264.7 macrophages. In these cells, stimulated with LPS, the test compounds decreased reactive oxygen species (ROS) production. They increased the cellular concentration of cAMP and attenuated the production of inflammatory cytokines such as $TNF\alpha$ and $IL-1\beta$. All results were comparable to those obtained for the reference compound JNJ7777120 with the exception of the impact on NO production. Nevertheless, this effect was similar to that obtained for the other reference compound rolipram, which is a phosphodiesterase 4 (PDE 4) inhibitor. Further experiments revealed that both of the investigated compounds possessed relatively low affinity for histamine H$_{1}$ receptor and do not inhibit the activity of the PDE 4B1 enzyme. In addition, all the effects of the investigated compounds in in vivo experiments were observed at doses that did not cause neurologic deficits in rotarod test and did not reduce spontaneous locomotor activity. Conclusions Our results demonstrate the anti-inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily $H_{4}R$-dependent

New spirohydantoin derivatives : synthesis, pharmacological evaluation and molecular modeling study

A series of new arylpiperazinylpropyl derivatives of 8/6-phenyl-1,3-diazaspiro[4.5]decan-2,4-dione and spiro[imidazolidine-4,1í-indene/naphthalene]-2,5-dione was synthesized and their affinity was evaluated toward serotonin 5-HT1A, 5-HT2A, 5-HT7 receptors, dopaminergic D2, D3 receptors, adrenergic α1 receptors, and serotonin transporter (SERT). The highest affinity for serotonin 5-HT1A/2A/7 receptors was found for compounds containing a tetralin or indane moiety in the imide part. Among these, two compounds (19, 20) were selected for further pharmacological in vivo studies. A binding mode of representative molecule 19, which behaved as a 5-HT1A agonist and weak 5-HT7 antagonist in the site of 5-HT1A/7, was also analyzed in computationa studies. Moreover, two highly selective (9 and 11) 5-HT2A receptor antagonists were obtained

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

KM-408, a novel phenoxyalkyl derivative as a potential anticonvulsant and analgesic compound for the treatment of neuropathic pain

BACKGROUND: Epilepsy frequently coexists with neuropathic pain. Our approach is based on the search for active compounds with multitarget profiles beneficial in terms of potential side effects and on the implementation of screening for potential multidirectional central activity. METHODS: Compounds were synthesized by means of chemical synthesis. After antiseizure and neurotoxicity screening in vivo, KM-408 and its enantiomers were chosen for analgesic activity evaluations. Further safety studies included acute toxicity in mice, the effect on normal electrocardiogram and on blood pressure in rats, whole body plethysmography in rats, and in vitro and biochemical assays. Pharmacokinetics has been studied in rats after iv and po administration. Metabolism has been studied in vivo in rat serum and urine. Radioligand binding studies were performed as part of the mechanism of action investigation. RESULTS: Selected results for KM-408: K(i) sigma = 7.2*10(–8); K(i) 5-HT(1A) = 8.0*10(–7); ED(50) MES (mice, ip) = 13.3 mg/kg; formalin test (I phase, mice, ip)—active at 30 mg/kg; SNL (rats, ip)—active at 6 mg/kg; STZ-induced pain (mice, ip)—active at 1 mg/kg (von Frey) and 10 mg/kg (hot plate); hot plate test (mice, ip)—active at 30 mg/kg; ED(50) capsaicin test (mice, ip) = 18.99 mg/kg; tail immersion test (mice)—active at 0.5%; corneal anesthesia (guinea pigs)—active at 0.125%; infiltration anesthesia (guinea pigs)—active at 0.125%. CONCLUSIONS: Within the presented study a novel compound, R,S-2-((2-(2-chloro-6-methylphenoxy)ethyl)amino)butan-1-ol hydrochloride (KM-408) with dual antiseizure and analgesic activity has been developed for potential use in neuropathic pain treatment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-022-00431-7

Interwencja kryzysowa : konteksty indywidualne i społeczne

Praca recenzowana / Peer-reviewed paperOddajemy dziś w Twoje ręce, Czytelniku, monografię, która w zamyśle redaktorów miała zostać poświęcona interwencji środowiskowej, tzw. nurtowi ekosystemu. Zamiaru tego nie udało się jednak w pełni zrealizować, z uwagi na stosunkowo niewielkie zainteresowanie polskich badaczy i praktyków teoretycznymi, jak i praktycznymi problemami interwencji kryzysowej społeczności i na rzecz społeczności, oraz jej specyfiką w polskich warunkach i realiach. Brak zainteresowania wydaje się po części wynikać z małego zaangażowania polskich służb pomocowych w nurty środowiskowej prewencji i działalności pomocowej. Ponad 20 lat rozwoju interwencji kryzysowej w naszym państwie zaowocowało rozbudową instytucjonalnych struktur interwencyjnych, a także przygotowaniem i kształceniem kadry interwentów kryzysowych, podejmujących się pomocy w sytuacjach kryzysowych i traumatycznych, w ramach instytucjonalnych powiązanych z pomocą społeczną, psychologiczną, rzadziej medyczną. Prezentowane w naszej monografii opracowania autorskie w pewien sposób odzwierciedlają problemy angażujące polskich interwentów kryzysu zarówno w aspekcie teoretycznym, jak praktyki interwencyjnej. Zanim jednak wprowadzimy Czytelników w problematykę poszczególnych opracowań monografii, chcielibyśmy pokrótce scharakteryzować stany kryzysowe, będące przedmiotem interwencyjnych oddziaływań ze współczesnej perspektywy ekologiczno-systemowej.Publikacja powstała w ramach projektu badawczego Krakowskiej Akademii im. Andrzeja Frycza Modrzewskiego nr WPiNH/DS/3/2015-KO