Karasova-Zdarova J

References (2)

Title : UHPLC-HRMS study of pharmacokinetics of a novel hybrid cholinesterase inhibitor K1234: A comparison between in silico, in vitro and in vivo data - Mzik_2022_J.Pharm.Biomed.Anal_219_114898
Author(s) : Mzik M , Sestak V , Mezeiova E , Korabecny J , Hroch M , Pejchal J , Karasova-Zdarova J
Ref : J Pharm Biomed Anal , 219 :114898 , 2022
Abstract : Alzheimer's disease (AD) is one of the most common forms of dementia. Current anti-AD therapeutics exploit the cholinergic hypothesis of its pathophysiology; they aim to inhibit cerebral cholinesterases. K1234 is a novel hybrid molecule derived from Huperzine A and 7-MEOTA-huperzine which shows increased potency in acetylcholinesterase inhibition in vitro compared to the compounds themselves. The study focused on description of the pharmacokinetic behaviour of K1234, blood-brain barrier penetration, identification of the main in vitro and in vivo metabolites. K1234 is relatively non-toxic compound, that is rapidly absorbed after i.p. administration reaching C(max) within minutes, with extensive distribution into tissues and fast metabolism in mice. The dominant metabolic pathway appears to be glucuronidation of the parent molecule and its phase-I metabolites. The passage of K1234 across the blood-brain-barrier in mice appears to be limited, as it reached only approximately one third of the AUC of plasma.
ESTHER : Mzik_2022_J.Pharm.Biomed.Anal_219_114898
PubMedSearch : Mzik_2022_J.Pharm.Biomed.Anal_219_114898
PubMedID: 35779353

Title : From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia - Mezeiova_2020_Bioorg.Chem_103_104179
Author(s) : Mezeiova E , Janockova J , Konecny J , Kobrlova T , Benkova M , Dolezal R , Prchal L , Karasova-Zdarova J , Soukup O , Korabecny J
Ref : Bioorg Chem , 103 :104179 , 2020
Abstract : YNT-185 is the first known small molecule acting as orexin 2 receptor (OX(2)R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX(2)R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX(2)R. We obtained seven new potential OX(2)R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX(2)R. Out of them, 15 emerged as the most potent modulator of OX(2)R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.
ESTHER : Mezeiova_2020_Bioorg.Chem_103_104179
PubMedSearch : Mezeiova_2020_Bioorg.Chem_103_104179
PubMedID: 32891860