Background/Objectives: Tacrine is a centrally active non-competitive reversible acetylcholinesterase inhibitor. It also exerts antagonising activity against N-methyl-D-aspartate receptors. Tacrine was approved for the treatment of Alzheimer's disease in 1993, but was withdrawn from clinical use in 2013 because of its hepatotoxicity and gastrointestinal side effects. Nevertheless, tacrine is currently facing a renewed wave of interest primarily due to several new tacrine-incorporated hybrids and derivates. There were two specific aims for this study: firstly, to explain the mechanisms of the adverse action of tacrine, as a distinctive example of a highly effective acetylcholinesterase inhibitor; and secondly to check whether luminal impedance planimetry is feasible for preclinical testing of possible side effects of compounds potentially toxic to the gastrointestinal tract. Methods: Six experimental pigs were used as the animal model in this study. Five major parameters were evaluated: luminal pressure (mmHg), estimated diameter (mm), cross-sectional area (mm2), distensibility (mm2/mmHg), and zone compliance (mm3/mmHg). All measurements were performed before and 360 min after intragastric administration of 200 mg tacrine (at the porcine tacrine Tmax). Results: This study consistently demonstrated an increase in luminal pressure (a directly measured indicator) for the particular balloon filling volumes used, and inversely a reciprocal decrease in the other parameters after tacrine administration. Conclusions: Endoscopic luminal impedance planimetry is a feasible method to evaluate functional response of the lower oesophageal sphincter to tacrine in experimental pigs. Tacrine did not compromise the function of the lower oesophageal sphincter either toward oesophageal spasms or, in contrast, decreased competence of the lower oesophageal sphincter.

• Klíčová slova
• Alzheimer’s disease, endoscopic luminal impedance planimetry, experimental pigs, lower oesophageal sphincter, tacrine,
• Publikační typ
• časopisecké články MeSH

Interindividual variability in drug response constitutes a major concern in pharmacotherapy. While polymorphisms in genes involved in drug disposition have been extensively studied, drug target variability remains underappreciated. By mapping the genomic variability of all human drug target genes onto high-resolution crystal structures of drug target complexes, we identified 1094 variants localized within 6 Å of drug-binding pockets and directly affecting their geometry, topology, or physicochemical properties. We experimentally show that binding site variants affect pharmacodynamics with marked drug- and variant-specific differences. In addition, we demonstrate that a common BCHE variant confers resistance to tacrine and rivastigmine, which can be overcome by the use of derivatives based on squaric acid scaffolds or tryptophan conjugation. These findings underscore the importance of genetic drug target variability and demonstrate that integration of genomic data and structural information can inform personalized drug selection and genetically guided drug development to overcome resistance.

• Publikační typ
• časopisecké články MeSH

A series of novel C4-C7-tethered biscoumarin derivatives (12a-e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood-brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer's disease.

• Klíčová slova
• A549, Alzheimer’s disease, antiproliferative activity, biscoumarin, blood–brain barrier, cholinesterase,
• MeSH
• aktivace enzymů účinky léků   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• buněčný cyklus účinky léků   MeSH
• buňky A549 MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• kumariny chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely * MeSH
• molekulární struktura MeSH
• techniky syntetické chemie * MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• cholinesterasové inhibitory MeSH
• kumariny MeSH

Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.

• Klíčová slova
• 9-O-demethyllycorenine, Alzheimer’s disease, Amaryllidaceae, narciabduliine,
• MeSH
• alkaloidy amarylkovitých chemie   farmakologie   MeSH
• alkaloidy chemie   farmakologie   MeSH
• Alzheimerova nemoc MeSH
• butyrylcholinesterasa chemie   ultrastruktura   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• cholinesterasy chemie   ultrastruktura   MeSH
• cirkulární dichroismus MeSH
• katalytická doména účinky léků   MeSH
• lidé MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• alkaloidy MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH

Thirteen known (1-12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13-15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.

• Klíčová slova
• Alzheimer’s disease, Amaryllidaceae, Narcissus pseudonarcissus cv. Carlton, alkaloids, butyrylcholinesterase, carltonine A–C, docking studies,
• MeSH
• alkaloidy chemie   farmakologie   MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• lidé MeSH
• Narcissus chemie   MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alkaloidy MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH