8 research outputs found
The 1,3,5-triazine derivatives as innovative chemical family of 5-HT6 serotonin receptor agents with therapeutic perspectives for cognitive impairment
Among serotonin receptors, the 5-HT6 subtype is the most controversial and the least
known in the field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative
treatment of cognitive impairment, but none has reached pharmacological market, predominantly,
due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were
identified as a new chemical family of potent 5-HT6R ligands. For the most active triazine
5-HT6R agents found (1-4), a wider binding profile and comprehensive in vitro evaluation of
their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were
investigated within this work. Results indicated the most promising pharmacological/druglikeness
profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) and
4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (4), which
displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests
in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative (4)
seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and
non-sulfone structure with the best 5-HT6R binding properties
Are the hydantoin-1,3,5-triazine ligands a hope to a find new procognitive and anti-obesity drug? : considerations based on primary in vivo assays and ADME-Tox profile in vitro
Though the serotonin receptor is an important target giving both agonists and
antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no ligand
has reached the pharmaceutical market yet due to the too narrow chemical space of the known
agents and insuffcient "drugability." Recently, a new group of non-indole and non-sulfone
hydantoin-triazine ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-
1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the
most active member. This study is focused on wider pharmacological and "druglikeness"
characteristics for KMP-10. A computer-aided insight into molecular interactions with
has been performed. "Druglikeness" was examined using an eight-test panel in vitro, i.e., a parallel
artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp)
affnity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well
as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated
plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on
the influence of KMP-10 on rats' metabolism, including biochemical tests, were conducted in vivo.
Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity
properties in vivo, and it was found to satisfy the "druglikeness" profile in vitro for KMP-10. The
compound seems to be a good lead-structure and candidate for wider pharmacological studies in
search for new CNS-drugs acting via
Evaluation of Whole-Cell and Acellular Pertussis Vaccines in the Context of Long-Term Herd Immunity
After the pertussis vaccine had been introduced in the 1940s and was shown to be very successful in reducing the morbidity and mortality associated with the disease, the possibility of improving both vaccine composition and vaccination schedules has become the subject of continuous interest. As a result, we are witnessing a considerable heterogeneity in pertussis vaccination policies, which remains beyond universal consensus. Many pertussis-related deaths still occur in low- and middle-income countries; however, these deaths are attributable to gaps in vaccination coverage and limited access to healthcare in these countries, rather than to the poor efficacy of the first generation of pertussis vaccine consisting in inactivated and detoxified whole cell pathogen (wP). In many, particularly high-income countries, a switch was made in the 1990s to the use of acellular pertussis (aP) vaccine, to reduce the rate of post-vaccination adverse events and thereby achieve a higher percentage of children vaccinated. However the epidemiological data collected over the past few decades, even in those high-income countries, show an increase in pertussis prevalence and morbidity rates, triggering a wide-ranging debate on the causes of pertussis resurgence and the effectiveness of current pertussis prevention strategies, as well as on the efficacy of available pertussis vaccines and immunization schedules. The current article presents a systematic review of scientific reports on the evaluation of the use of whole-cell and acellular pertussis vaccines, in the context of long-term immunity and vaccines efficacy
Novel Aryloxyethyl Derivatives of 1(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5HT1A Receptor-Biased Agonists with Robust Antidepressant-like Activity
Novel
1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed
as “biased agonists” of serotonin 5-HT1A receptors.
The compounds were tested in signal transduction assays (ERK1/2 phosphorylation,
cAMP inhibition, Ca2+ mobilization, and β-arrestin
recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl
derivatives. The novel series showed high 5-HT1A receptor
affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, serotonin 5-HT2A, histamine
H1, and muscarinic M1 receptors, and favorable
druglike properties (CNS-MPO, Fsp3, LELP). The lead structure,
(3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone
(17, NLX-204), displayed high selectivity in the SafetyScreen44
panel (including hERG channel), high solubility, metabolic stability,
and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes,
or P-glycoprotein. Preliminary in vivo studies confirmed its promising
pharmacokinetic profile. 17 also robustly stimulated
ERK1/2 phosphorylation in rat cortex and showed highly potent (MED
= 0.16 mg/kg) and efficacious antidepressant-like activity, totally
eliminating immobility in the rat Porsolt test. These data suggest
that the present 5-HT1A receptor-biased agonists could
constitute promising antidepressant drug candidates