Malikowska-Racia N

References (3)

Title : Novel object recognition test as an alternative approach to assessing the pharmacological profile of sigma-1 receptor ligands - Szczepanska_2023_Pharmacol.Rep__
Author(s) : Szczepanska K , Bojarski AJ , Popik P , Malikowska-Racia N
Ref : Pharmacol Rep , : , 2023
Abstract : BACKGROUND: Although the terms "agonist" and "antagonist" have been used to classify sigma-1 receptor (sigma(1)R) ligands, an unambiguous definition of the functional activity is often hard. In order to determine the pharmacological profile of sigma(1)R ligands, the most common method is to assess their potency to alleviate opioid analgesia. It has been well established that sigma(1)R agonists reduce opioid analgesic activity, while sigma(1)R antagonists have been demonstrated to enhance opioid analgesia in different pain models. METHODS: In the present study, we evaluated the pharmacological profile of selected sigma(1)R ligands using a novel object recognition (NOR) test, to see if any differences in cognitive functions between sigma(1)R agonists and antagonists could be observed. We used the highly selective PRE-084 and S1RA as reference sigma(1)R agonist and antagonist, respectively. Furthermore, compound KSK100 selected from our ligand library was also included in this study. KSK100 was previously characterized as a dual-targeting histamine H(3)/sigma(1)R antagonist with antinociceptive and antiallodynic activity in vivo. Donepezil (acetylcholinesterase inhibitor and sigma(1)R agonist) was used as a positive control drug. RESULTS: Both tested sigma(1)R agonists (donepezil and PRE-084) improved learning in the NOR test, which was not observed with the sigma(1)R antagonists S1RA and KSK100. CONCLUSIONS: The nonlinear dose-response effect of PRE-084 in this assay does not justify its use for routine assessment of the functional activity of sigma(1)R ligands.
ESTHER : Szczepanska_2023_Pharmacol.Rep__
PubMedSearch : Szczepanska_2023_Pharmacol.Rep__
PubMedID: 37572216

Title : Structure-activity relationship study of tryptophan-based butyrylcholinesterase inhibitors - Meden_2020_Eur.J.Med.Chem_208_112766
Author(s) : Meden A , Knez D , Malikowska-Racia N , Brazzolotto X , Nachon F , Svete J , Salat K , Groselj U , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 208 :112766 , 2020
Abstract : A series of tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors was designed and synthesized. Compounds were optimized in terms of potency, selectivity, and synthetic accessibility. The crystal structure of the inhibitor 18 in complex with BChE revealed the molecular basis for its low nanomolar inhibition (IC50 = 2.8 nM). The favourable in vitro results enabled a first-in-animal in vivo efficacy and safety trial, which demonstrated a positive impact on fear-motivated and spatial long-term memory retrieval without any concomitant adverse motor effects. Altogether, this research culminated in a handful of new lead compounds with promising potential for symptomatic treatment of patients with Alzheimers disease.
ESTHER : Meden_2020_Eur.J.Med.Chem_208_112766
PubMedSearch : Meden_2020_Eur.J.Med.Chem_208_112766
PubMedID: 32919297
Gene_locus related to this paper: human-BCHE

Title : Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives - Jonczyk_2019_Bioorg.Chem_90_103084
Author(s) : Jonczyk J , Lodarski K , Staszewski M , Godyn J , Zareba P , Soukup O , Janockova J , Korabecny J , Salat K , Malikowska-Racia N , Hebda M , Szalaj N , Filipek B , Walczynski K , Malawska B , Bajda M
Ref : Bioorg Chem , 90 :103084 , 2019
Abstract : In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2=8.27), inhibitory activity against both AChE (IC50=13.96muM), and BuChE (IC50=14.62muM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.
ESTHER : Jonczyk_2019_Bioorg.Chem_90_103084
PubMedSearch : Jonczyk_2019_Bioorg.Chem_90_103084
PubMedID: 31271942