Marcin Kołaczkowski | Jagiellonian University in Krakow (original) (raw)

Papers by Marcin Kołaczkowski

Acta Crystallographica Section C Structural Chemistry, 2018

Nowadays, a search for antagonists co-acting on serotonin receptor subtypes 6 and 7 (5-HT6R and 5... more Nowadays, a search for antagonists co-acting on serotonin receptor subtypes 6 and 7 (5-HT6R and 5-HT7R, respectively) is of great interest due to the increasing number of patients suffering from dementia and related behavioural and psychological symptoms. The X-ray crystal structures of four promising multifunctional ligands in the hydrochloride forms were determined, namely 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-methylbenzenesulfonamido)propyl]piperidin-1-ium chloride, C22H27FN3O3S+·Cl−, (I), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C25H28F2N3O3S2 +·Cl−, (II), 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[4-(6-fluorobenzo[b]thiophene-2-sulfonamido)butyl]piperidin-1-ium chloride, C24H26ClFN3O3S2 +·Cl−, (III), and 4-(6-fluoro-1,2-benzoxazol-3-yl)-1-[3-(3-chloro-4-fluorobenzenesulfonamido)propyl]piperidin-1-ium chloride, C21H22ClF2N3O3S2 +·Cl−, (IV). Two pharmacologically important functional groups, i.e. arylsulfo...

International Journal of Molecular Sciences

Neurodegeneration leading to Alzheimer’s disease results from a complex interplay of a variety of... more Neurodegeneration leading to Alzheimer’s disease results from a complex interplay of a variety of processes including misfolding and aggregation of amyloid beta and tau proteins, neuroinflammation or oxidative stress. Therefore, to address more than one of these, drug discovery programmes focus on the development of multifunctional ligands, preferably with disease-modifying and symptoms-reducing potential. Following this idea, herein we present the design and synthesis of multifunctional ligands and biological evaluation of their 5-HT6 receptor affinity (radioligand binding assay), cholinesterase inhibitory activity (spectroscopic Ellman’s assay), antioxidant activity (ABTS assay) and metal-chelating properties, as well as a preliminary ADMET properties evaluation. Based on the results we selected compound 14 as a well-balanced and potent 5-HT6 receptor ligand (Ki = 22 nM) and human BuChE inhibitor (IC50 = 16 nM) with antioxidant potential expressed as a reduction of ABTS radicals b...

European Journal of Medicinal Chemistry, 2022

Neuropsychiatric symptoms (NPS), such as psychosis, depression and anxiety are frequently observe... more Neuropsychiatric symptoms (NPS), such as psychosis, depression and anxiety are frequently observed among patients with dementia. NPS is treated by off-label psychotropic medications that are only modestly effective in dementia patients, with a high risk of adverse events and cognitive decline. Considering the above, there is an unmet need for a well-tolerated and effective therapy of NPS in dementia. We designed and synthesized a library of dual-acting compounds as phosphodiesterase type-10A inhibitors and serotonin 5-HT1AR ligands. The most potent molecules, compounds 4 and 8, as partial agonists of 5-HT1AR and PDE10A inhibitors, exhibited a very high permeability of the blood-brain barrier. Compounds 4 and 8 displayed antipsychotic- and antidepressant-like activity and restored recognition memory deficits in mice. The overall effectiveness, pharmacokinetic and bioavailability studies imply the therapeutic-like potential of the presented dual-acting compounds as a method of treatment of NPS in dementia.

European Journal of Medicinal Chemistry, 2021

Multifunctional ligands as an essential variant of polypharmacology are promising candidates for ... more Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT6R antagonists (Ki = 13 nM and Ki = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC50 = 8 nM and IC50 = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC50 = 455 nM). Both compounds inhibit aggregation of amyloid β in vitro (75% for compound 17 and 68% for 35 at 10 μM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 μM and lack of toxicity on HepG2 cell line (IC50 values of 80 and 21 μM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.

CNS Drugs, 2020

Along with cognitive decline, 90% of patients with dementia experience behavioral and psychologic... more Along with cognitive decline, 90% of patients with dementia experience behavioral and psychological symptoms of dementia, such as psychosis, aggression, agitation, and depression. Atypical antipsychotics are commonly prescribed off-label to manage certain symptoms, despite warnings from the regulatory agencies regarding the increased risk of mortality associated with their use in elderly patients. Moreover, these compounds display a limited clinical efficacy, mostly owing to the fact that they were developed to treat schizophrenia, a disease characterized by neurobiological deficits. Thus, to improve clinical efficacy, it has been suggested that patients with dementia should be treated with exclusively designed and developed drugs that interact with pharmacologically relevant targets. Within this context, numerous studies have suggested druggable targets that might achieve therapeutically acceptable pharmacological profiles. Based on this, several different drug candidates have been proposed that are being investigated in clinical trials for behavioral and psychological symptoms of dementia. We highlight the recent advances toward the development of therapeutic agents for dementia-related psychosis and agitation/ aggression and discuss the relationship between the relevant biological targets and their etiology. In addition, we review the compounds that are in the early stage of development (discovery or preclinical phase) and those that are currently being investigated in clinical trials for dementia-related psychosis and agitation/aggression. We also discuss the mechanism of action of these compounds and their pharmacological utility in patients with dementia.

Expert Opinion on Drug Discovery, 2018

Introduction: Cariprazine is approved in the United States and Europe for the treatment of manic ... more Introduction: Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult patients. It is typically administered orally once a day (a dose range 1.5-6 mg/day), does require titration, and may be given with or without food. It has a half-life of 2-4 days with an active metabolite that has a terminal half-life of 2-3 weeks. Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. This article is based on the available literature with respect to the preclinical and clinical findings and product labels of cariprazine. Expert opinion: Cariprazine shows highest affinity toward D 3 receptors, followed by D 2 , 5-HT 2B , and 5-HT 1A receptors. It also shows moderate affinity toward σ 1 , 5-HT 2A , and histamine H 1 receptors. Longterm administration of cariprazine altered the abundance of dopamine, serotonin, and glutamate receptor subtypes in different brain regions. All these mechanisms of cariprazine may contribute toward its unique preclinical profile and its clinically observed benefits in the treatment of schizophrenia, bipolar mania, and possibly other psychiatric disorders.

Bioorganic & Medicinal Chemistry, 2019

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Metabolic Brain Disease, 2018

Obesity, from early childhood onwards, is a common societal problem. The overconsumption of sweet... more Obesity, from early childhood onwards, is a common societal problem. The overconsumption of sweet, salty and high-fat products are the main factors that cause excessive weight gain. It is therefore necessary to search for new drugs that affect satiety centers and reduce the sense of hunger and caloric intake. It has been suggested that the blockade of 5-HT 6 receptors may reduce food intake, and since idalopirdine is a clinically tested, selective 5HT 6 receptor antagonist, it was chosen to be examined in animal models of obesity. The activity of idalopirdine was measured in the rat model of excessive eating. Animals were on a high caloric diet that consisted of milk chocolate with nuts, cheese, salted peanuts and condensed milk. During a four-week experiment, the rats had constant access to standard feed and water ad libitum. Idalopirdine was administered intraperitoneally at a dose 5 mg/kg b.w./day. To establish whether idalopirdine would effectively suppress the rebound hyperphagia that accompanies refeeding, it was administered after a 20 h food deprivation period. Pica behavior was evaluated after the administration of idalopirdine to confirm that the suppression of food intake was not caused by visceral illness. The effect of the four-week treatment with idalopirdine on the amount of peritoneal adipose tissue, and on lipid and carbohydrate profiles in rats was also examined. The statistical significance was calculated using the one-way ANOVA post-hoc Tukey Multiple Comparison Test or the two-way ANOVA post-hoc Bonferroni Multiple Comparison Test. Idalopirdine significantly reduced caloric intake and prevented the development of obesity in tested animals. Rats, that received idalopirdine, had a smaller amount of adipose tissue in the peritoneum as well as lower glucose, triglyceride and cholesterol levels in comparison to the control group. Moreover, an anorectic action was not caused by abnormalities of the gastrointestinal tract, such as nausea. The obtained results indicate that idalopirdine reduces caloric intake and could be considered for further tests as a potential treatment of obesity.

Journal of Medicinal Chemistry, 2019

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of se... more Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT 1A receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca 2+ mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT 1A receptor affinity, >1000-fold selectivity versus noradrenergic α 1 , dopamine D 2 , serotonin 5-HT 2A , histamine H 1 , and muscarinic M 1 receptors, and favorable druglike properties (CNS-MPO, Fsp 3 , 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-HT 1A receptor-biased agonists could constitute promising antidepressant drug candidates.

Naunyn-Schmiedeberg's Archives of Pharmacology, 2017

The effect of some antidepressants co-administered with EMD386088 in the modified forced swim tes... more The effect of some antidepressants co-administered with EMD386088 in the modified forced swim test in rats was investigated. Additionally, the pharmacokinetics, metabolic stability, and the effect of EMD386088 on P450 cytochromes were determined. Intraperitoneal (i.p.) coadministration of EMD386088 (2.5 mg/kg) and imipramine (15 mg/kg), reboxetine (5 mg/kg), moclobemide (10 mg/kg), or bupropion (10 mg/kg) evoked significant antidepressant-like activity, whereas no effect was observed after joint administration of EMD386088 with s-citalopram (10 mg/kg). Pharmacokinetic in vivo investigation showed a rapid absorption of EMD386088 (2.5 and 5 mg/kg) with t 1/2 = 67 min (tmax = 5 min). Large volume of distribution (V d /F = 102 L/ kg) indicated its penetration into peripheral compartments. The most active coadministration of EMD386088 (2.5 mg/ kg) with imipramine (15 mg/kg) resulted in slower absorption of the compound (C max = 60 min) and decrease in the volume of distribution (V d /F = 32.2 L/kg). EMD386088 penetrates the blood-brain barrier with a high brain/plasma ratio of about 19 (2.5 mg/kg) and 7.5 for coadministration with imipramine. The in silico and in vitro studies on EMD386088 metabolic stability showed the dehydrogenation of tetrahydropyridine moiety as its main metabolic pathway. EMD386088 did not influence on CYP3A4 activity, and it has been classified as a very weak CYP2D6 inhibitor (IC 50 = 2.25 μM). The results obtained from the forced swim test in rats indicate that an activation of 5HT 6 receptor may facilitate antidepressant-like activity of some antidepressants. The pharmacokinetic results suggest that the interaction between EMD386088 and imipramine could not have been pharmacokinetic in nature.

ACS chemical neuroscience, Jan 16, 2018

Alzheimer's disease (AD) is a major public health problem, which is due to its increasing pre... more Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT receptors ( K = 18 nM) and noncompetitive inhibitor of cholinesterases (IC = 14 nM, IC = 22 nM). In further in vitro studies, compound 12 has shown amyloid β antiaggregation activity (IC = 1.27 μM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.

European Journal of Medicinal Chemistry, 2016

HT 6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on t... more HT 6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT 6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT 6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT 6 receptor (K b = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC 50 hAChE = 12 nM, IC 50 hBuChE = 29 nM). The compound also showed good in vitro blood-brainbarrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD.

Metabolic Brain Disease, 2016

The use of atypical antipsychotic drugs like olanzapine is associated with side effects such as s... more The use of atypical antipsychotic drugs like olanzapine is associated with side effects such as sedation and depression-like symptoms, especially during the initial period of the use. It is believed that the occurrence of these undesirable effectsis mainly the result of the histamine H 1 receptors blockade by olanzapine. In addition, use of olanzapine increases the level of triglycerides in the blood, which correlates with growing obesity. The aim of this study was to investigate the influence of pitolisant-H 3 histamine antagonist-on subchronic olanzapine-induced depresion-like symptoms, sedation and hypertriglicerydemia. Forced swim test was conducted to determinate depressive-like effect of olanzapine and antidepressive-like activity during the coadministered pitolisant. The test was performed after the first and fifteenth day of the treatment of the mice. The spontaneous activity of the mice was measured on the fourteenth day of the treatment with a special, innovative RFID-system (Radiofrequency identification system)-TraffiCage (TSE-Systems, Germany). Triglyceride levels were determined on the sixteenth day of the experiment after 15 cycles of drug administration. Daily olanzapine treatment (4 mg/kg b.w., i.p., d.p.d) for 15 days significantly induces sedation (p < 0.05) and prolongs immobility time in forced swim tests (FST) in mice (p < 0.05); and also elevates the level of triglycerides (p < 0.05). Administration of pitolisant (10 mg/kg b.w., i.p.) subsequentto olanzapine normalizes these adverse effects. This study presents a promising alternative for counteracting some behavioral changes and metabolic disturbances which occur in the early period of treatment with antipsychotic drugs.

Psychiatria, 2014

Niezadowalające efekty farmakoterapii schizofrenii, szczególnie w zakresie redukcji objawów negat... more Niezadowalające efekty farmakoterapii schizofrenii, szczególnie w zakresie redukcji objawów negatywnych i poznawczych, stanowią impuls do poszukiwania i opracowania nowych leków przeciwpsychotycznych, o wyższej skuteczności i bezpieczniejszym profilu działania. Jedną z wiodących strategii jest poszukiwanie nowych leków o wieloreceptorowym mechanizmie działania, które oprócz blokady receptorów dopaminergicznych D 2 , będą wpływać na przekaźnictwo serotoninergiczne (antagonizm wobec receptorów 5-HT 2A , agonizm/częściowy agonizm wobec receptorów 5-HT 1A , antagonizm wobec receptorów 5-HT 6 i/lub 5-HT 7), przy jednoczesnym, słabym oddziaływaniu z receptorami histaminowymi i cholinergicznymi [1, 2]. Wynikiem prowadzonych w takim kierunku prac badawczo-rozwojowych było wprowadzenie w październiku 2010 roku na amerykański rynek farmaceutyczny lurasidonu, nowego leku przeciwpsychotycznego II generacji (SGA, second generation antipsychotic) [3]. Dnia 23 stycznia 2014 roku komisja Committee for Medicinal Products for Human Use (CHMP), przygotowująca dla European Medicines Agency (EMA) opinie odnośnie do wprowadzenia leków na rynek europejski, opublikowała pozytywną rekomendację dla stosowania lurasidonu w schizofrenii u pacjentów powyżej 18. roku życia.

Archiv der Pharmazie, Jan 8, 2016

β-Adrenergic receptor antagonists are important therapeutics for the treatment of cardiovascular ... more β-Adrenergic receptor antagonists are important therapeutics for the treatment of cardiovascular disorders. In the group of β-blockers, much attention is being paid to the third-generation drugs that possess important ancillary properties besides inhibiting β-adrenoceptors. Vasodilating activity of these drugs is produced through different mechanisms, such as nitric oxide (NO) release, β2 -agonistic action, α1 -blockade, antioxidant action, and Ca(2+) entry blockade. Here, a study on evaluation of the cardiovascular activity of five new compounds is presented. Compound 3a is a methyl and four of the tested compounds (3b-e) are dimethoxy derivatives of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol. The obtained results confirmed that the methyl and dimethoxy derivatives of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and their enantiomers possess α1 - and β1 -adrenolytic activities and that the antiarrhythmic and hypotensive effects of the t...

Naunyn-Schmiedeberg's Archives of Pharmacology, 2015

Postępy Psychiatrii i Neurologii, 2014

ABSTRACT Recent studies on the pathomechanism of Alzheimer's disease have shown profound ... more ABSTRACT Recent studies on the pathomechanism of Alzheimer's disease have shown profound alterations in GABA signaling in brains of dementia patients. GABA is the major inhibitory neurotransmitter in the brain, responsible for controlling other neurotransmitter systems. Deficits in GABAergic transmission may lead to cognitive impairments and to behavioral and psychological symptoms of Alzheimer's dementia. Therefore GABAergic transmissionas may be considered as a viable target for novel anti-dementia drugs. Several projects have been initiated worldwide searching for selective ligands of the GABA-A receptor subunits and multimodal substances acting at different neurotransmitter systems, including the GABA-A receptor. Results of preclinical studies and preliminary data from clinical trials tend to indicate that GABA-A receptor ligands may be potential therapeutic agents for the treatment of Alzheimer's disease.

European Journal of Medicinal Chemistry, 2015