Papers by Agnieszka Olejarz
Pharmaceutics
The clinical symptoms of Parkinson’s disease (PD) appear when dopamine (DA) concentrations in the... more The clinical symptoms of Parkinson’s disease (PD) appear when dopamine (DA) concentrations in the striatum drops to around 20%. Simultaneous inhibitory effects on histamine H3 receptor (H3R) and MAO B can increase DA levels in the brain. A series of compounds was designed and tested in vitro for human H3R (hH3R) affinity and inhibitory activity to human MAO B (hMAO B). Results showed different activity of the compounds towards the two biological targets. Most compounds had poor affinity for hH3R (Ki > 500 nM), but very good inhibitory potency for hMAO B (IC50 < 50 nM). After further in vitro testing (modality of MAO B inhibition, permeability in PAMPA assay, cytotoxicity on human astrocyte cell lines), the most promising dual-acting ligand, 1-(3-(4-(tert-butyl)phenoxy)propyl)-2-methylpyrrolidine (13: hH3R: Ki = 25 nM; hMAO B IC50 = 4 nM) was selected for in vivo evaluation. Studies in rats of compound 13, in a dose of 3 mg/kg of body mass, confirmed its antagonistic effects fo...
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
International Journal of Molecular Sciences, 2021
Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important ... more Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with benefi...
European Journal of Medicinal Chemistry, 2020
Design and development of multitarget-directed ligands (MTDLs) has become a very important approa... more Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H 3 receptor (H 3 R) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human H 3 R (hH 3 R) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hH 3 R affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC 50 values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hH 3 R (K i ¼ 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC 50 ¼ 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC 50 ¼ 880 nM and 394 nM respectively) and hMAO B (IC 50 ¼ 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hH 3 R, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.
European Journal of Medicinal Chemistry, 2020
The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to add... more The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking 5-HT6R scaffolds with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay and artificial membrane permeability, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.
International Journal of Molecular Sciences, 2020
Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A comb... more Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H3R (hH3R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH3R affinities with Ki values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH3R: Ki = 38 nM and hMAO B: IC50 = 48 nM). Thus, DL76 was chosen for further studies, re...
Bioorganic Chemistry, 2020
A library of 34 novel compounds based on a xanthine scaffold was explored in biological studies f... more A library of 34 novel compounds based on a xanthine scaffold was explored in biological studies for interaction with adenosine receptors (ARs). Structural modifications of the xanthine core were introduced in the 8-position (benzylamino and benzyloxy substitution) as well as at N1, N3, and N7 (small alkyl residues), thereby improving affinity and selectivity for the A 2A AR. The compounds were characterized by radioligand binding assays, and our study resulted in the development of the potent A 2A AR ligands including 8-((6-chloro-2-fluoro-3-methoxybenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12d; K i human A 2A AR: 68.5 nM) and 8-((2-chlorobenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12h; K i human A 2A AR: 71.1 nM). Moreover, dual A 1 /A 2A AR ligands were identified in the group of 1,3-diethyl-7-methylxanthine derivatives. Compound 14b displayed K i values of 52.2 nM for the A 1 AR and 167 nM for the A 2A AR. Selected A 2A AR ligands were further evaluated as inactive for inhibition of monoamine oxidase A, B and isoforms of phosphodiesterase-4B1,-10A, which represent classical targets for xanthine derivatives. Therefore, the developed 8-benzylaminoxanthine scaffold seems to be highly selective for AR activity and relevant for potent and selective A 2A ligands. Compound 12d with high selectivity for ARs, especially for the A 2A AR subtype, evaluated in animal models of inflammation has shown anti-inflammatory activity. Investigated compounds were found to display high selectivity and may therefore be of high interest for further development as drugs for treating cancer or neurodegenerative diseases.
ChemMedChem, 2020
Annelated purinedione derivatives have been shown to act as possible multiple‐target ligands, add... more Annelated purinedione derivatives have been shown to act as possible multiple‐target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido‐ and diazepino[2,1‐f]purinedione derivatives were designed as dual‐target‐directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO‐B. This allowed 9‐(2‐chloro‐6‐fluorobenzyl)‐3‐ethyl‐1‐methyl‐6,7,8,9‐tetrahydropyrimido[2,1‐f]purine‐2,4(1H,3H)‐dione (13 e; Ki human A2AAR: 264 nM and IC50 human MAO‐B: 243 nM) to be identified as the most potent dual‐acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure‐activity relationships was complemented by molecular‐docking studies based on previously published X‐ray structures of the protein targets. Such dual‐acting ligands, by selectively blocking A2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO‐B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease
Biochemical Pharmacology, 2019
Aims: Histamine H 3 receptors ligands act anorectic by blocking the H 3 autoreceptors in the CNS,... more Aims: Histamine H 3 receptors ligands act anorectic by blocking the H 3 autoreceptors in the CNS, that results in increased synthesis and disinhibition of histamine release. Histamine further influencing H 1 receptors participates in the leptin-dependent inhibition of food intake. It also affects the peripheral metabolism by increasing white adipose tissue lipolysis. Thus, ligands such as KSK19 with significant antagonistic properties at the H 3 receptor might serve as an useful treatment for obesity. Materials and methods: To induce obesity, female CD-1 mice were fed a high-fat diet for 14 weeks. The test compound at the doses of 10 or 15 mg/kg, i.p. was administrated for 21 days. Glucose and insulin tolerance tests was performed at the beginning of week 15. At the end of study, amount of intraperitoneal fat pads, AlAT, IL-6 and TNF-α plasma levels were determined. Results: Animals fed with high-fat diet and treated with test compound at the dose of 15 mg/kg showed significantly less weight gain, than mice from the control group. The use of KSK19 for 21 days in obese mice also significantly improved glucose tolerance and insulin resistance. In the tested doses KSK19 did not affect locomotor activity neither in lean nor in obese mice after single i.p. administration, but spontaneous activity increased during three hour after twentieth administrations. Conclusion: KSK19 is a strong, selective histamine H 3 receptor antagonist with a favorable influence on body weight after multiple administration at the dose of 15 mg/kg. Moreover it significantly improves glucose tolerance.
Bioorganic Chemistry, 2019
Structural modifications and in vitro pharmacological evaluation of 4-pyridyl-piperazine derivati... more Structural modifications and in vitro pharmacological evaluation of 4-pyridyl-piperazine derivatives as an active and selective histamine H 3 receptor ligands, Bioorganic Chemistry (2019), doi:
Bioorganic & Medicinal Chemistry, 2019
Novel multi-target directed ligands based on annelated xanthine scaffold with aromatic substituen... more Novel multi-target directed ligands based on annelated xanthine scaffold with aromatic substituents acting on adenosine receptor and monoamine oxidase B.
Bioorganic & Medicinal Chemistry Letters, 2018
The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in ... more The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H 3 receptor affinity with K i values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC 50 value of 4.5 nM. In addition, hMAO B inhibition by 5 was shown to be non-competitive and reversible. Further, recently described potent histamine H 3 receptor ligands-4-tert
European journal of medicinal chemistry, Jan 15, 2018
GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively exp... more GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date. Analogs were synthesized that exhibit broad modifications of the heterocyclic core and/or variation of substituents at the benzylidene moiety. The compounds were investigated in β-arrestin recruitment assays as inhibitors of human GPR18 activation by tetrahydrocannabinol (THC). Selectivity was assessed versus the cannabinoid receptors (CB and CB) and versus GPR55, another orphan GPCR that interacts with cannabinoids. Phenyloxyalkyloxy-substituted benzylidenethiazinones...
Molecules, 2021
Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging... more Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultan...
European journal of medicinal chemistry, Jan 25, 2018
As a continuation of our search for novel histamine H receptor ligands, a series of twenty four n... more As a continuation of our search for novel histamine H receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H receptor (hHR). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (K = 16.0-120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional HR antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental ...
Molecules (Basel, Switzerland), Jan 8, 2017
In view of the pressing need to identify new antibacterial agents able to combat multidrug-resist... more In view of the pressing need to identify new antibacterial agents able to combat multidrug-resistant bacteria, we investigated a series of fused selenazolinium derivatives (-) regarding their in vitro antimicrobial activities against 25 ESKAPE-pathogen strains. Ebselen was used as reference compound. Most of the selenocompounds demonstrated an excellent in vitro activity against all strains, with activities comparable to or even exceeding the one of ebselen. In contrast to ebselen, some selenazolinium derivatives (, , and ) even displayed significant actions against all Gram-negative pathogens tested. The 3-bromo-2-(1-hydroxy-1-methylethyl)[1,2]selenazolo[2,3-]pyridinium chloride () was particularly active (minimum inhibitory concentrations, MICs: 0.31-1.24 µg/mL for MRSA, and 0.31-2.48 µg/mL for Gram-negative bacteria) and devoid of any significant mutagenicity in the Ames assay. Our preliminary mechanistic studies in cell culture indicated that their mode of action is likely to be...
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British journal of pharmacology, Jan 27, 2018
The histaminergic system is a promising target for the development of new analgesics, since expre... more The histaminergic system is a promising target for the development of new analgesics, since expression of histamine H R and H R receptors has been reported in regions related to nociceptive transmission. The aim of our study was to determine the analgesic effects of new H R and H R antagonists in naive and neuropathic (CCI, chronic constriction injury) male and female mice. We investigated the effects of newly synthesized H R (E-162; 1-(5-(naphthalen-1-yloxy)pentyl)piperidine) and H R (TR-7; 4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) antagonists on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli in naive and CCI-exposed (7 days after injury) animals. We evaluated the effects of antagonists on morphine analgesia and also investigated the participation of H R in drugs effects. We analyzed the compounds in binding and functional cAMP assays at the H R/H R and determined metabolic stability. E-162 and TR-7 attenuated nociceptive responses and...
Chemical Biology & Drug Design
Since the year 1993, when 5-HT7 receptor (5-HT7 R) was discovered, there is no selective 5-HT7 R ... more Since the year 1993, when 5-HT7 receptor (5-HT7 R) was discovered, there is no selective 5-HT7 R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5-HT7 R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by &quot;drug-likeness&quot; estimation of the first series of selective and potent 5-HT7 R ligands among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-aryl-piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione derivatives (11-16). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test (FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2. The experiments showed promising drug-like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13. The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant-like activity in the FST. Taking into account the beneficial properties of 13, i.e., good drug-like parameters, the significant antagonistic action, high selectivity to 5-HT7 R, and its in vivo antidepressant-like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5-HT7 receptor.
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Papers by Agnieszka Olejarz