Publications by authors named "Annamaria Lubelska"

26 Publications

  • Page 1 of 1

Cyanobiphenyls: Novel H receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease.

Bioorg Chem 2021 09 28;114:105129. Epub 2021 Jun 28.

Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, Krakow 30-688, Poland. Electronic address:

Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1'-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of K values) for human histamine H receptors (hHR) and good nonselective inhibitory potency (micromolar range of IC values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hHR/eeAChE/eqBuChE/hMAO B ligand (5: hHR K = 9.2 nM; eeAChE IC = 2.63 µM; eqBuChE IC = 1.30 µM; hMAO B IC = 0.60 µM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.
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http://dx.doi.org/10.1016/j.bioorg.2021.105129DOI Listing
September 2021

Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria.

Int J Mol Sci 2021 Feb 19;22(4). Epub 2021 Feb 19.

Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, ul. Medyczna 9, 30-688 Krakow, Poland.

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (-) were tested for oxacillin adjuvant properties in the Methicillin-susceptible (MSSA) strain ATCC 25923 and Methicillin-resistant MRSA 19449. Compounds - were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of to determine the potential of compounds - to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (, ) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (). The 4-phenylbenzylidene derivative () demonstrated significant MDR-reversal "dual action" for -lactam antibiotics in MRSA and inhibited AcrAB-TolC in . displayed also satisfied solubility and safety towards CYP3A4 in vitro.
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http://dx.doi.org/10.3390/ijms22042062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922564PMC
February 2021

Design and Synthesis of Novel Aminoalkanamides Targeting Neurodegeneration and Symptoms of Alzheimer's Disease.

Curr Med Chem 2021 ;28(29):6082-6094

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688 Krakow, Poland.

Background: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties.

Objective: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT/5-HT receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease.

Methods: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against HO-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively.

Results: Synthesized aminoalkanamides were characterized as potent 5-HTreceptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability.

Conclusion: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease.
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http://dx.doi.org/10.2174/0929867328666210215113346DOI Listing
September 2021

The relationship between stereochemical and both, pharmacological and ADME-Tox, properties of the potent hydantoin 5-HTR antagonist MF-8.

Bioorg Chem 2021 01 10;106:104466. Epub 2020 Nov 10.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. Electronic address:

This study concerns synthesis and evaluation of pharmacodynamic and pharmacokinetic profile for all four stereoisomers of MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione), the previously described, highly potent 5-HTR ligand with antidepressant activity on mice. The combination of DFT calculations of H NMR chemical shifts with docking and dynamic simulations, in comparison to experimental screening results, provided prediction of the configuration for one of two present stereogenic centers. The experimental data for stereoisomers (MF-8A-MF-8D) confirmed the significant impact of stereochemistry on both, 5-HTR affinity and antagonistic action, with K and K values in the range of 3-366 nM and 0.024-99 μM, respectively. We also indicated the stereochemistry-dependent influence of the tested compounds on P-glycoprotein efflux, absorption in Caco-2 model, metabolic pathway as well as CYP3A4 and CYP2C9 activities.
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http://dx.doi.org/10.1016/j.bioorg.2020.104466DOI Listing
January 2021

Novel anilide and benzylamide derivatives of arylpiperazinylalkanoic acids as 5-HT/5-HT receptor antagonists and phosphodiesterase 4/7 inhibitors with procognitive and antidepressant activity.

Eur J Med Chem 2020 Sep 17;201:112437. Epub 2020 Jun 17.

Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, 9 Medyczna Street, 30-688, Kraków, Poland. Electronic address:

A library of novel anilide and benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acids as combined 5-HT/5-HT receptor ligands and phosphodiesterase PDE4B/PDE7A inhibitors was designed using a structure-based drug design approach. The in vitro studies of 33 newly synthesized compounds (7-39) allowed us to identify 22 as the most promising multifunctional 5-HT/5-HT receptor antagonist (5-HTK = 8 nM, K = 0.04 nM; 5-HTK = 451 nM, K = 460 nM) with PDE4B/PDE7A inhibitory activity (PDE4B IC = 80.4 μM; PDE7A IC = 151.3 μM). Compound 22 exerted a very good ability to passively penetrate through biological membranes and a high metabolic stability in vitro. Moreover, the pharmacological evaluation of 22 showed its procognitive and antidepressant properties in rat behavioral tests. Compound 22 at a dose of 3 mg/kg (i.p.) significantly reversed MK-801-induced episodic memory deficits in the novel object recognition test, while at a dose of 10 mg/kg (i.p.) reduced the immobility time of animals (by about 34%) in the forced swimming test. The antidepressant-like effect produced by compound 22 was stronger than that of escitalopram used as a reference drug. This study opens a new perspective in the search for efficacious drugs for the treatment of cognitive and depressive disorders.
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http://dx.doi.org/10.1016/j.ejmech.2020.112437DOI Listing
September 2020

Multitargeted Compounds Derived from (2,5-Dioxopyrrolidin-1-yl)(phenyl)-Acetamides as Candidates for Effective Anticonvulsant and Antinociceptive Agents.

ACS Chem Neurosci 2020 07 17;11(13):1996-2008. Epub 2020 Jun 17.

Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.

We developed a focused set of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant and antinociceptive properties. These hybrid compounds demonstrated broad-spectrum protective activity in a range of mouse models, such as the maximal electroshock (MES) test, the pentylenetetrazole-induced seizures (PTZ), and the 6 Hz (32 mA) seizures. Compound showed the most potent anticonvulsant activity (ED MES = 23.7 mg/kg, ED 6 Hz (32 mA) = 22.4 mg/kg, ED PTZ = 59.4 mg/kg). In addition, revealed potent efficacy in the formalin-induced tonic pain. These activities of are likely mediated by several targets and may result from the inhibition of central sodium/calcium currents and transient receptor potential vanilloid 1 (TRPV1) receptor antagonism. Finally, the lead compound revealed drug-like absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) properties in the assays, making it a potential candidate for further development in epilepsy and neuropathic pain indications.
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http://dx.doi.org/10.1021/acschemneuro.0c00257DOI Listing
July 2020

Are the Hydantoin-1,3,5-triazine 5-HTR Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro.

Molecules 2019 Dec 6;24(24). Epub 2019 Dec 6.

Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland.

Though the 5-HT serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HTR ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HTR agents and insufficient "drugability." Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HTR ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and "druglikeness" characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HTR has been performed. "Druglikeness" was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug-drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats' metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the "druglikeness" profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HTR.
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http://dx.doi.org/10.3390/molecules24244472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943527PMC
December 2019

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug.

Neurotherapeutics 2020 01;17(1):309-328

Department of Animal Physiology, Institute of Biology and Biochemistry, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033, Lublin, Poland.

In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZ-induced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM).
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http://dx.doi.org/10.1007/s13311-019-00773-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007424PMC
January 2020

Structural modifications and in vitro pharmacological evaluation of 4-pyridyl-piperazine derivatives as an active and selective histamine H receptor ligands.

Bioorg Chem 2019 10 20;91:103071. Epub 2019 Jun 20.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland. Electronic address:

A novel series of 4-pyridylpiperazine derivatives with varying alkyl linker length and eastern part substituents proved to be potent histamine H receptor (hHR) ligands in the nanomolar concentration range. While paying attention to their alkyl linker length, derivatives with a six methylene linker tend to be more potent than their five methylene homologues. Moreover, in the case of both phenoxyacetyl- and phenoxypropionyl- derivatives, an eight methylene linkers possess lower activity than their seven methylene homologues. However, in global analysis of collected data on the influence of alkyl linker length, a three methylene homologues appeared to be of highest hHR affinity among all described 4-pyridylpiperazine derivatives from our group up to date. In the case of biphenyl and benzophenone derivatives, compounds with para- substituted second aromatic ring were of higher affinity than their meta analogues. Interestingly, benzophenone derivative 18 showed the highest affinity among all tested compounds (hHR K = 3.12 nM). The likely protein-ligand interactions, responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at HR, as well as drug-like properties of selected ligands were evaluated using in vitro methods.
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http://dx.doi.org/10.1016/j.bioorg.2019.103071DOI Listing
October 2019

The 1,3,5-Triazine Derivatives as Innovative Chemical Family of 5-HT Serotonin Receptor Agents with Therapeutic Perspectives for Cognitive Impairment.

Int J Mol Sci 2019 Jul 12;20(14). Epub 2019 Jul 12.

Department of Technology and Biotechnology of Drugs, Medical College, Jagiellonian University, Medyczna 9, PL 30-688 Cracow, Poland.

Among serotonin receptors, the 5-HT subtype is the most controversial and the least known in the field of molecular mechanisms. The 5-HTR ligands can be pivotal for innovative treatment of cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient "druglikeness" properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family of potent 5-HTR ligands. For the most active triazine 5-HTR agents found (-), a wider binding profile and comprehensive in vitro evaluation of their drug-like parameters as well as behavioral studies and an influence on body mass in vivo were investigated within this work. Results indicated the most promising pharmacological/druglikeness profiles for 4-((1H-indol-3-yl)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine () and 4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (), which displayed a significant procognitive action and specific anxiolytic-like effects in the behavioral tests in vivo together with satisfied pharmaceutical and safety profiles in vitro. The thymol derivative () seems to be of higher importance as a new lead candidate, due to the innovative, non-indole and non-sulfone structure with the best 5-HTR binding properties.
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http://dx.doi.org/10.3390/ijms20143420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678253PMC
July 2019

Synthesis and computer-aided SAR studies for derivatives of phenoxyalkyl-1,3,5-triazine as the new potent ligands for serotonin receptors 5-HT.

Eur J Med Chem 2019 Sep 10;178:740-751. Epub 2019 Jun 10.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Kraków, Poland. Electronic address:

This research has provided the most active 5-HTR agents among 1,3,5-triazine derivatives investigated to date and has also identified the world's first selenium-containing 5-HTR ligands. The studies are focused on design, synthesis, biological evaluation and docking-supported SAR analysis for novel 5-HTR agents as derivatives of lead structure 4-(4-methylpiperazin-1-yl)-6-(phenoxymethyl)-1,3,5-triazin-2-amine (7). The lead modifications included an introduction of: (i) various small substituents at benzene ring, (ii) a branched ether linker or (iii) the ether oxygen replacement with other chalcogen (S, Se) or sulfonyl moiety. Hence, a series of new compounds (7-24) was synthesized and examined on their affinities for 5-HTR and selectivity, in respect to the 5-HTR, 5-HTR, 5-HTR and dopamine D receptor, in the radioligand binding assays. For representative most active compounds functional bioassays and toxicity profile in vitro and antidepressant-like activity in vivo were examined. The 2-isopropyl-5-methylphenyl derivative (10) was found as the most active triazine 5-HTR antagonist (K = 11 nM). SAR analysis indicated, that an exchange of oxygen to selenium (7 vs. 22), and especially, to sulfur (7 vs. 19) was beneficial to increase both affinity and antagonistic action for 5-HTR. Surprisingly, an introduction of SO caused a drastic decrease of the 5-HTR affinity, which was explained at a molecular level based on docking studies. All in vivo tested compounds (10, 18 and 21) did not show any risk of toxicity in the safety studies in vitro.
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http://dx.doi.org/10.1016/j.ejmech.2019.06.022DOI Listing
September 2019

5-Arylideneimidazolones with Amine at Position 3 as Potential Antibiotic Adjuvants against Multidrug Resistant Bacteria.

Molecules 2019 Jan 26;24(3). Epub 2019 Jan 26.

Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland.

Searching for new chemosensitizers of bacterial multidrug resistance (MDR), chemical modifications of (Z)-5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one () were performed. New compounds (⁻), with fused aromatic rings at position 5, were designed and synthesized. Crystallographic X-ray analysis proved that the final compounds (⁻) were substituted with tertiary amine-propyl moiety at position 3 and primary amine group at 2 due to intramolecular Dimroth rearrangement. New compounds were evaluated on their antibiotic adjuvant properties in either Gram-positive or Gram-negative bacteria. Efflux pump inhibitor (EPI) properties towards the AcrAB-TolC pump in (EA289) were investigated in the real-time efflux (RTE) assay. Docking and molecular dynamics were applied to estimate an interaction of compounds ⁻ with penicillin binding protein (PBP2a). In vitro ADME-Tox properties were evaluated for compound . Most of the tested compounds reduced significantly (4-32-fold) oxacillin MIC in highly resistant MRSA HEMSA 5 strain. The anthracene-morpholine derivative () was the most potent (32-fold reduction). The tested compounds displayed significant EPI properties during RTE assay (37⁻97%). The naphthyl-methylpiperazine derivative showed the most potent "dual action" of both oxacillin adjuvant (MRSA) and EPI (). Molecular modeling results suggested the allosteric mechanism of action of the imidazolones, which improved binding of oxacillin in the PBP2a active site in MRSA.
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http://dx.doi.org/10.3390/molecules24030438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384991PMC
January 2019

Search for a 5-CT alternative. and evaluation of novel pharmacological tools: 3-(1-alkyl-1-imidazol-5-yl)-1-indole-5-carboxamides, low-basicity 5-HT receptor agonists.

Medchemcomm 2018 Nov 25;9(11):1882-1890. Epub 2018 Sep 25.

Institute of Pharmacology , Polish Academy of Sciences , 12 Smętna Street , 31-343 Kraków , Poland.

Close structural analogues of 5-carboxamidotryptamine (5-CT) based on the newly discovered indole-imidazole scaffold were synthesized and evaluated to search for a 5-HT receptor agonist of higher selectivity. drug-likeness studies and pharmacological evaluation of potent and selective low-basicity 5-HT receptor agonists, previously published (3-(1-ethyl-1-imidazol-5-yl)-1-indole-5-carboxamide, AH-494) and (3-(1-methyl-1-imidazol-5-yl)-1-indole-5-carboxamide), have supported their usefulness as pharmacological tools. Comprehensive comparison studies between , and the commonly used 5-CT showed their very similar ADMET properties. Compound at 1 mg kg reversed MK-801-induced disruption in novel object recognition in mice and alleviated stress-induced hyperthermia (SIH) at high doses. Taking into account both and data, and may be considered as alternatives to 5-CT as pharmacological tools with important additional benefit associated with their low-basicity: high selectivity over 5-HTR.
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http://dx.doi.org/10.1039/c8md00313kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256855PMC
November 2018

Optimization and preclinical evaluation of novel histamine Hreceptor ligands: Acetyl and propionyl phenoxyalkyl piperazine derivatives.

Bioorg Med Chem 2018 12 10;26(23-24):6056-6066. Epub 2018 Nov 10.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland. Electronic address:

As a continuation of our search for novel histamine H receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H receptors (hHR). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hHR affinity (hHR K = 5.2-115 nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hHR K = 5.2 and 15.4 nM vs. 10.2 and 115 nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed.
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http://dx.doi.org/10.1016/j.bmc.2018.11.010DOI Listing
December 2018

Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats.

Int J Mol Sci 2018 Oct 29;19(11). Epub 2018 Oct 29.

Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE.

A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (⁻) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.). However, only H3R antagonist without appreciable protective effects in MES- and PTZ-induced seizure, fully protected animals in the strychnine (STR)-induced GTCS following acute systemic pretreatment (10 mg/kg, i.p.). Moreover, the protective effect observed with H3R antagonist in MES-induced seizure was completely abolished when animals were co-administered with the H3R agonist ()-α-methylhistamine (RAMH, 10 mg/kg, i.p.). However, RAMH failed to abolish the full protection provided by the H3R antagonist in PTZ-induced seizure and H3R antagonist in STR-induced seizure. Furthermore, in vitro antiproliferative effects or possible metabolic interactions could not be observed for compound . Additionally, the predictive in silico, as well as in vitro, metabolic stability for the most promising H3R antagonist was assessed. The obtained results show prospective effects of non-imidazole H3R antagonists as innovative antiepileptic drugs (AEDs) for potential single use against epilepsy.
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http://dx.doi.org/10.3390/ijms19113386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274786PMC
October 2018

Computer-Aided Studies for Novel Arylhydantoin 1,3,5-Triazine Derivatives as 5-HT₆ Serotonin Receptor Ligands with Antidepressive-Like, Anxiolytic and Antiobesity Action In Vivo.

Molecules 2018 Oct 3;23(10). Epub 2018 Oct 3.

Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland.

This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines, with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT₆, 5-HT, 5-HT, 5-HT₇, and dopamine D₂ receptors were evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT₆ receptor conformation space employing two lead structures. It resulted in a consistent binding mode with the activity data. For the most active compounds found in each modification line, anti-obesity and anti-depressive-like activity in vivo, as well as "druglikeness" in vitro, were examined. Two 2-naphthyl compounds ( and ) were identified as the most active 5-HT₆R agents within each lead modification line, respectively. The 5-(2-naphthyl)hydantoin derivative , the most active one in the series (5-HT₆R: = 87 nM), displayed also significant selectivity towards competitive G-protein coupled receptors (6⁻197-fold). Docking studies indicated that the hydantoin ring is stabilized by hydrogen bonding, but due to its different orientation, the hydrogen bonds form with S5.44 and N6.55 or Q6.58 for and , respectively. Compound exerted anxiolytic-like and antidepressant-like activities. Importantly, it demonstrated anti-obesity properties in animals fed palatable feed, and did not show toxic effects in vitro.
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http://dx.doi.org/10.3390/molecules23102529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222450PMC
October 2018

KA-11, a Novel Pyrrolidine-2,5-dione Derived Broad-Spectrum Anticonvulsant: Its Antiepileptogenic, Antinociceptive Properties and in Vitro Characterization.

ACS Chem Neurosci 2019 01 10;10(1):636-648. Epub 2018 Oct 10.

Department of Medicinal Chemistry, Faculty of Pharmacy , Jagiellonian University Medical College , Medyczna 9 , 30-688 Kraków , Poland.

Recently, compound KA-11 was identified as a promising candidate for a new broad-spectrum anticonvulsant. This compound revealed wide protective activity across the most important animal models of seizures such as the maximal electroshock test (MES), the subcutaneous pentylenetetrazole test ( scPTZ), and the six-hertz test (6 Hz, 32 mA). Importantly, KA-11 was devoid of acute neurological activity, which was assessed by applying the chimney test (TD value higher than 1500 mg/kg). The preliminary in vivo results confirmed favorable anticonvulsant and safety properties of KA-11. With the aim of further biological characterization of KA-11, in the current studies we evaluated its antiepileptogenic activity in the kindling model of epilepsy induced by repeated injection of PTZ in mice. Furthermore, we assessed the antinociceptive activity of KA-11 in several animal pain models. As a result, KA-11 (at all doses applied: 25, 50, and 100 mg/kg) significantly delayed the progression of kindling induced by repeated injection of PTZ in mice. Additionally, KA-11 revealed potent antinociceptive activity in the formalin-induced tonic pain and, importantly, in the oxaliplatin-induced neuropathic pain model in mice. Moreover, KA-11 did not induce motor deficits in the rotarod test. Patch-clamp experiments revealed that one of the mechanisms of action of KA-11 is inhibition of voltage-gated sodium currents. Compound KA-11 appeared to be safe in relation to hepatotoxic properties as no phospholipidosis induction was determined in HepG2 cells at 50 μM, and a small, statistically significant decrease of cell viability was observed only at the highest used dose of 100 μM. Moreover, KA-11 did not affect the function of CYP2D6. The aforementioned hybrid substance proved to penetrate the biological membranes in the in vitro permeability assays.
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http://dx.doi.org/10.1021/acschemneuro.8b00476DOI Listing
January 2019

The role of aryl-topology in balancing between selective and dual 5-HTR/5-HT actions of 3,5-substituted hydantoins.

Medchemcomm 2018 Jun 8;9(6):1033-1044. Epub 2018 May 8.

Department of Technology and Biotechnology of Drugs , Jagiellonian University Medical College , Medyczna 9 , 30-688 Cracow , Poland . Email: ; Tel: +012 620 55 80.

In order to search for active and selective serotonin 5-HTR antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of the introduction/deletion and the mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure of 3-(3-(4-(diphenylmethyl)piperazin-1-yl)-2-hydroxypropyl)-5-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione (, KKB16) were performed. New derivatives () were designed and synthesized. X-ray crystallographic analysis of the representative compound 5-(4-fluorophenyl)-3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl]-5-methylimidazolidine-2,4-dione () was performed to support molecular modeling and SAR studies. The affinity for 5-HTR, DR and 5-HTR in radioligand binding assays for the entire series and ADME-Tox parameters for selected compounds (, , and ) were evaluated. Molecular docking and pharmacophore model assessment were performed. According to the obtained results, 5-methyl-5-naphthylhydantoin derivatives were found to be the new highly active 5-HTR agents ( ≤ 5 nM) with significant selectivity over 5-HTR and DR. On the contrary, the (1-naphthyl)piperazine moiety was gained with the potent dual 5-HTR/5-HTR action (: 11 nM/19 nM).
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http://dx.doi.org/10.1039/c8md00168eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072329PMC
June 2018

2-Phenylquinoline S. aureus NorA Efflux Pump Inhibitors: Evaluation of the Importance of Methoxy Group Introduction.

J Med Chem 2018 09 17;61(17):7827-7848. Epub 2018 Aug 17.

Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy.

Antimicrobial resistance (AMR) represents a hot topic in drug discovery. Besides the identification of new antibiotics, the use of nonantibiotic molecules to block resistance mechanisms is a powerful alternative. Bacterial efflux pumps exert an early step in AMR development by allowing bacteria to grow at subinhibitorial drug concentrations. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR. Given our experience in developing Staphylococcus aureus NorA EPIs, in this work, starting from the 2-phenylquinoline hit 1, we planned the introduction of methoxy groups on the basis of their presence in known NorA EPIs. Among the 35 different synthesized derivatives, compounds 3b and 7d exhibited the best NorA inhibition activity by restoring at very low concentrations ciprofloxacin MICs against resistant S. aureus strains. Interestingly, both compounds displayed EPI activities at nontoxic concentrations for human cells as well as highlighted promising results by preliminary pharmacokinetic studies.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00791DOI Listing
September 2018

Anticonvulsant evaluation of novel non-imidazole histamine H3R antagonists in different convulsion models in rats.

Pharmacol Biochem Behav 2018 07 3;170:14-24. Epub 2018 May 3.

Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates. Electronic address:

Novel non-imidazole histamine H3 receptor (H3R) antagonists (2-8) were developed and assessed for in-vitro antagonist binding affinities at the human histamine H1-H4R. These novel H3R antagonists (2-8) were examined in-vivo for anticonvulsant effects in three different convulsion models in male adult rats. Compound 6 significantly and dose-dependently exhibited decreased duration of tonic hind limb extension (THLE) in the maximal electroshock (MES)- and fully protected animals against pentylenetetrazole (PTZ)-induced convulsion, following acute systemic administration (5, 10, and 20 mg/kg, i.p.). Contrary, all compounds 2-8 showed moderate protection in the strychnine (STR)-induced convulsion model following acute pretreatment (10 mg/kg, i.p.). Moreover, the acute systemic administration of H3R antagonist 6 (10 mg/kg, i.p.) significantly prolonged latency time for MES convulsions. Furthermore, the anticonvulsant effect observed with compound 6 in MES-model was entirely abrogated when rats were co-injected with the brain penetrant H1R antagonist pyrilamine (PYR) but not the brain penetrant H2R antagonist zolantidine (ZOL). However, PYR and ZOL failed to abolish the full protection provided by the H3R antagonist 6 in PTZ- and STR-models. No mutagenic or antiproliferative effects or potential metabolic interactions were shown for compound 6 when assessing its antiproliferative activities and metabolic profiling applying in-vitro methods. These findings demonstrate the potential of non-imidazole H3R antagonists as novel antiepileptic drugs (AEDs) either for single use or in addition to currently available epilepsy medications.
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http://dx.doi.org/10.1016/j.pbb.2018.04.010DOI Listing
July 2018

Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine HR ligands.

Eur J Med Chem 2018 May 25;152:223-234. Epub 2018 Apr 25.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland. Electronic address:

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 evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in HR ligands.
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http://dx.doi.org/10.1016/j.ejmech.2018.04.043DOI Listing
May 2018

Novel naphthyloxy derivatives - Potent histamine H receptor ligands. Synthesis and pharmacological evaluation.

Bioorg Med Chem 2018 05 11;26(9):2573-2585. Epub 2018 Apr 11.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address:

A series of 1- and 2-naphthyloxy derivatives were synthesized and evaluated for histamine H receptor affinity. Most compounds showed high affinities with K values below 100 nM. The most potent ligand, 1-(5-(naphthalen-1-yloxy)pentyl)azepane (11) displayed high affinity for the histamine H receptor with a K value of 21.9 nM. The antagonist behaviour of 11 was confirmed both in vitro in the cAMP assay (IC = 312 nM) and in vivo in the rat dipsogenia model (ED = 3.68 nM). Moreover, compound 11 showed positive effects on scopolamine induced-memory deficits in mice (at doses of 10 and 15 mg/kg) and an analgesic effect in the formalin test in mice with ED = 30.6 mg/kg (early phase) and ED = 20.8 mg/kg (late phase). Another interesting compound, 1-(5-(Naphthalen-1-yloxy)pentyl)piperidine (13; HR K = 53.9 nM), was accepted for Anticonvulsant Screening Program at the National Institute of Neurological Disorders and Stroke/National Institute of Health (Rockville, USA). The screening was performed in the maximal electroshock seizure (MES), the subcutaneous pentylenetetrazole (scPTZ) and the 6-Hz psychomotor animal models of epilepsy. Neurologic deficit was evaluated by the rotarod test. Compound 13 inhibited convulsions induced by the MES with ED of 19.2 mg/kg (mice, i.p.), 17.8 (rats, i.p.), and 78.1 (rats, p.o.). Moreover, 13 displayed protection against the 6-Hz psychomotor seizures (32 mA) in mice (i.p.) with ED of 33.1 mg/kg and (44 mA) ED of 57.2 mg/kg. Furthermore, compounds 11 and 13 showed in vitro weak influence on viability of tested cell lines (normal HEK293, neuroblastoma IMR-32, hepatoma HEPG2), weak inhibition of CYP3A4 activity, and no mutagenicity. Thus, these compounds may be used as leads in a further search for histamine H receptor ligands with promising in vitro and in vivo activity.
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http://dx.doi.org/10.1016/j.bmc.2018.04.023DOI Listing
May 2018

MF-8, a novel promising arylpiperazine-hydantoin based 5-HT receptor antagonist: In vitro drug-likeness studies and in vivo pharmacological evaluation.

Bioorg Med Chem Lett 2018 03 3;28(5):878-883. Epub 2018 Feb 3.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address:

We report the in vitro drug-likeness studies and in vivo pharmacological evaluation for a new potent 5-HT receptor antagonist MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylhydantoin). The in vitro tests showed good permeability, very good metabolic stability, low risk of drug-drug interactions and satisfying safety profile. Moreover, MF-8 showed excellent antidepressant-like activity in the forced swim test in rodents and promising anxiolytic-like activity in the four-plate test in mice. Regarding the potent affinity, high selectivity and antagonistic activity of MF-8 for the 5-HT receptor as well as excellent drug - like properties in vitro and confirmed in vivo pharmacological activity, MF-8 should be considered as a very significant molecule in the search for a new class of anti-depressant drugs.
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http://dx.doi.org/10.1016/j.bmcl.2018.02.003DOI Listing
March 2018

In the search for a lead structure among series of potent and selective hydantoin 5-HT R agents: The drug-likeness in vitro study.

Chem Biol Drug Des 2017 Dec 3;90(6):1295-1306. Epub 2017 Oct 3.

Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Kraków, Poland.

Since the year 1993, when 5-HT receptor (5-HT R) was discovered, there is no selective 5-HT R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5-HT R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by "drug-likeness" estimation of the first series of selective and potent 5-HT 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-HT 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-HT receptor.
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http://dx.doi.org/10.1111/cbdd.13106DOI Listing
December 2017

Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H receptor ligands.

Bioorg Med Chem 2017 10 29;25(20):5341-5354. Epub 2017 Jul 29.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, ul. Medyczna 9, 30-688 Kraków, Poland. Electronic address:

Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a K value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; K=25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; K=34nM), classified as antagonists in a cAMP accumulation assay (IC=4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hHR vs hHR>600-fold) and low toxicity (hERG inhibition: IC>1.70µM; hepatotoxicity IC>12.5µM; non-mutagenic up to 10µM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring.
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http://dx.doi.org/10.1016/j.bmc.2017.07.058DOI Listing
October 2017

Rational design in search for 5-phenylhydantoin selective 5-HT7R antagonists. Molecular modeling, synthesis and biological evaluation.

Eur J Med Chem 2016 Apr 9;112:258-269. Epub 2016 Feb 9.

Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address:

A series of novel arylpiperazine 5-(4-fluorophenyl)-5-methylhydantoins with 2-hydroxypropyl linker (2-15) was synthesized and evaluated on their affinity towards serotonin 5-HT7 receptor (5-HT7R) in comparison to other closely related GPCRs: serotonin 5-HT1A, and dopamine D2 receptors. The functional activity studied through the measurement of 5-HT7R-mediated cyclic AMP production in Human Embryonic Kidney 293 cells (HEK293) stably expressing human 5-HT7 proved their antagonistic properties. The lead structure was also examined in the preliminary metabolic stability study using human liver microsomes (HMLs). The process of selection of candidates for synthesis was supported by a special molecular modeling workflow including combinatorial library generation, docking, and machine learning-based assessment. Additionally, in silico predictions of selectivity over 5-HT1AR and D2R, as well as functional activity were carried out. The newly synthesized compounds were proved to possess a potent affinity for 5-HT7R, similar to that of the lead structure of 5-(4-fluorophenyl)-3-(3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)-5-methylimidazolidine-2,4-dione (1). For several derivatives, significant selectivity both over 5-HT1AR and D2R was found.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.024DOI Listing
April 2016
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