TY  - JOUR
AU  - Butini, Stefania
AU  - Nikolić, Katarina
AU  - Kassel, S.
AU  - Brueckmann, H.
AU  - Filipić, Slavica
AU  - Agbaba, Danica
AU  - Gemma, S.
AU  - Brogi, S.
AU  - Brindisi, M.
AU  - Campiani, G.
AU  - Stark, Holger
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2738
AB  - Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinson's disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - Progress in Neurobiology
T1  - Polypharmacology of dopamine receptor ligands
VL  - 142
SP  - 68
EP  - 103
DO  - 10.1016/j.pneurobio.2016.03.011
ER  - 

@article{
author = "Butini, Stefania and Nikolić, Katarina and Kassel, S. and Brueckmann, H. and Filipić, Slavica and Agbaba, Danica and Gemma, S. and Brogi, S. and Brindisi, M. and Campiani, G. and Stark, Holger",
year = "2016",
abstract = "Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinson's disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "Progress in Neurobiology",
title = "Polypharmacology of dopamine receptor ligands",
volume = "142",
pages = "68-103",
doi = "10.1016/j.pneurobio.2016.03.011"
}

Butini, S., Nikolić, K., Kassel, S., Brueckmann, H., Filipić, S., Agbaba, D., Gemma, S., Brogi, S., Brindisi, M., Campiani, G.,& Stark, H.. (2016). Polypharmacology of dopamine receptor ligands. in Progress in Neurobiology
Pergamon-Elsevier Science Ltd, Oxford., 142, 68-103.
https://doi.org/10.1016/j.pneurobio.2016.03.011

Butini S, Nikolić K, Kassel S, Brueckmann H, Filipić S, Agbaba D, Gemma S, Brogi S, Brindisi M, Campiani G, Stark H. Polypharmacology of dopamine receptor ligands. in Progress in Neurobiology. 2016;142:68-103.
doi:10.1016/j.pneurobio.2016.03.011 .

Butini, Stefania, Nikolić, Katarina, Kassel, S., Brueckmann, H., Filipić, Slavica, Agbaba, Danica, Gemma, S., Brogi, S., Brindisi, M., Campiani, G., Stark, Holger, "Polypharmacology of dopamine receptor ligands" in Progress in Neurobiology, 142 (2016):68-103,
https://doi.org/10.1016/j.pneurobio.2016.03.011 . .

TY  - JOUR
AU  - Nikolić, Katarina
AU  - Mavridis, Lazaros
AU  - Đikić, Teodora
AU  - Vučićević, Jelica
AU  - Agbaba, Danica
AU  - Yelekci, Kemal
AU  - Mitchell, John B. O.
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2540
AB  - The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug discovery programs. A probabilistic method, the ParzenRosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D-1-R/D-2-R/5-HT2A-R/H-3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Neuroscience
T1  - Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies
VL  - 10
DO  - 10.3389/fnins.2016.00265
ER  - 

@article{
author = "Nikolić, Katarina and Mavridis, Lazaros and Đikić, Teodora and Vučićević, Jelica and Agbaba, Danica and Yelekci, Kemal and Mitchell, John B. O.",
year = "2016",
abstract = "The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug discovery programs. A probabilistic method, the ParzenRosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D-1-R/D-2-R/5-HT2A-R/H-3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Neuroscience",
title = "Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies",
volume = "10",
doi = "10.3389/fnins.2016.00265"
}

Nikolić, K., Mavridis, L., Đikić, T., Vučićević, J., Agbaba, D., Yelekci, K.,& Mitchell, J. B. O.. (2016). Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies. in Frontiers in Neuroscience
Frontiers Media Sa, Lausanne., 10.
https://doi.org/10.3389/fnins.2016.00265

Nikolić K, Mavridis L, Đikić T, Vučićević J, Agbaba D, Yelekci K, Mitchell JBO. Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies. in Frontiers in Neuroscience. 2016;10.
doi:10.3389/fnins.2016.00265 .

Nikolić, Katarina, Mavridis, Lazaros, Đikić, Teodora, Vučićević, Jelica, Agbaba, Danica, Yelekci, Kemal, Mitchell, John B. O., "Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies" in Frontiers in Neuroscience, 10 (2016),
https://doi.org/10.3389/fnins.2016.00265 . .

TY  - JOUR
AU  - Khanfar, Mohammad A.
AU  - Affini, Anna
AU  - Lutsenko, Kiril
AU  - Nikolić, Katarina
AU  - Butini, Stefania
AU  - Stark, Holger
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2547
AB  - With the very recent market approval of pitolisant (Wakix (R)), the interest in clinical applications of novel multifunctional histamine H-3 receptor antagonists has clearly increased. Since histamine H-3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H-3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Neuroscience
T1  - Multiple Targeting Approaches on Histamine H-3 Receptor Antagonists
VL  - 10
DO  - 10.3389/fnins.2016.00201
ER  - 

@article{
author = "Khanfar, Mohammad A. and Affini, Anna and Lutsenko, Kiril and Nikolić, Katarina and Butini, Stefania and Stark, Holger",
year = "2016",
abstract = "With the very recent market approval of pitolisant (Wakix (R)), the interest in clinical applications of novel multifunctional histamine H-3 receptor antagonists has clearly increased. Since histamine H-3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H-3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Neuroscience",
title = "Multiple Targeting Approaches on Histamine H-3 Receptor Antagonists",
volume = "10",
doi = "10.3389/fnins.2016.00201"
}

Khanfar, M. A., Affini, A., Lutsenko, K., Nikolić, K., Butini, S.,& Stark, H.. (2016). Multiple Targeting Approaches on Histamine H-3 Receptor Antagonists. in Frontiers in Neuroscience
Frontiers Media Sa, Lausanne., 10.
https://doi.org/10.3389/fnins.2016.00201

Khanfar MA, Affini A, Lutsenko K, Nikolić K, Butini S, Stark H. Multiple Targeting Approaches on Histamine H-3 Receptor Antagonists. in Frontiers in Neuroscience. 2016;10.
doi:10.3389/fnins.2016.00201 .

Khanfar, Mohammad A., Affini, Anna, Lutsenko, Kiril, Nikolić, Katarina, Butini, Stefania, Stark, Holger, "Multiple Targeting Approaches on Histamine H-3 Receptor Antagonists" in Frontiers in Neuroscience, 10 (2016),
https://doi.org/10.3389/fnins.2016.00201 . .

TY  - JOUR
AU  - Hughes, Rebecca E.
AU  - Nikolić, Katarina
AU  - Ramsay, Rona R.
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2592
AB  - Alzheimer's Disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs (MTDs). Intended as an introduction for non-experts, this review describes the key MID design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch, and the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer's Disease are rasagiline, originally developed for the treatment of Parkinson's Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Neuroscience
T1  - One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug
VL  - 10
DO  - 10.3389/fnins.2016.00177
ER  - 

@article{
author = "Hughes, Rebecca E. and Nikolić, Katarina and Ramsay, Rona R.",
year = "2016",
abstract = "Alzheimer's Disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs (MTDs). Intended as an introduction for non-experts, this review describes the key MID design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch, and the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer's Disease are rasagiline, originally developed for the treatment of Parkinson's Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Neuroscience",
title = "One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug",
volume = "10",
doi = "10.3389/fnins.2016.00177"
}

Hughes, R. E., Nikolić, K.,& Ramsay, R. R.. (2016). One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug. in Frontiers in Neuroscience
Frontiers Media Sa, Lausanne., 10.
https://doi.org/10.3389/fnins.2016.00177

Hughes RE, Nikolić K, Ramsay RR. One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug. in Frontiers in Neuroscience. 2016;10.
doi:10.3389/fnins.2016.00177 .

Hughes, Rebecca E., Nikolić, Katarina, Ramsay, Rona R., "One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug" in Frontiers in Neuroscience, 10 (2016),
https://doi.org/10.3389/fnins.2016.00177 . .

TY  - JOUR
AU  - Nikolić, Katarina
AU  - Filipić, Slavica
AU  - Agbaba, Danica
AU  - Stark, Holger
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2196
AB  - The histamine H-3 receptor (H3R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3R antagonists/inverse agonists involved studies of structure-activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H-3 autoreceptors reinforces histaminergic transmission, while antagonism of H-3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3R antagonists/inverse agonists and dual H3R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.
PB  - Wiley, Hoboken
T2  - CNS Neuroscience & Therapeutics
T1  - Procognitive Properties of Drugs with Single and Multitargeting H-3 Receptor Antagonist Activities
VL  - 20
IS  - 7
SP  - 613
EP  - 623
DO  - 10.1111/cns.12279
ER  - 

@article{
author = "Nikolić, Katarina and Filipić, Slavica and Agbaba, Danica and Stark, Holger",
year = "2014",
abstract = "The histamine H-3 receptor (H3R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3R antagonists/inverse agonists involved studies of structure-activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H-3 autoreceptors reinforces histaminergic transmission, while antagonism of H-3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3R antagonists/inverse agonists and dual H3R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.",
publisher = "Wiley, Hoboken",
journal = "CNS Neuroscience & Therapeutics",
title = "Procognitive Properties of Drugs with Single and Multitargeting H-3 Receptor Antagonist Activities",
volume = "20",
number = "7",
pages = "613-623",
doi = "10.1111/cns.12279"
}

Nikolić, K., Filipić, S., Agbaba, D.,& Stark, H.. (2014). Procognitive Properties of Drugs with Single and Multitargeting H-3 Receptor Antagonist Activities. in CNS Neuroscience & Therapeutics
Wiley, Hoboken., 20(7), 613-623.
https://doi.org/10.1111/cns.12279

Nikolić K, Filipić S, Agbaba D, Stark H. Procognitive Properties of Drugs with Single and Multitargeting H-3 Receptor Antagonist Activities. in CNS Neuroscience & Therapeutics. 2014;20(7):613-623.
doi:10.1111/cns.12279 .

Nikolić, Katarina, Filipić, Slavica, Agbaba, Danica, Stark, Holger, "Procognitive Properties of Drugs with Single and Multitargeting H-3 Receptor Antagonist Activities" in CNS Neuroscience & Therapeutics, 20, no. 7 (2014):613-623,
https://doi.org/10.1111/cns.12279 . .

TY  - JOUR
AU  - Bautista-Aguilera, Oscar M.
AU  - Esteban, Gerard
AU  - Chioua, Mourad
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
AU  - Moraleda, Ignacio
AU  - Iriepa, Isabel
AU  - Soriano, Elena
AU  - Samadi, Abdelouahid
AU  - Unzeta, Mercedes
AU  - Marco-Contelles, Jose
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2083
AB  - The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] = 1.1 +/- 0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 = 600 +/- 80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] = 5,700 +/- 2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] = 3,950 +/- 94 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD.
PB  - Dove Medical Press Ltd, Albany
T2  - Drug Design Development and Therapy
T1  - Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids
VL  - 8
SP  - 1893
EP  - 1910
DO  - 10.2147/DDDT.S69258
ER  - 

@article{
author = "Bautista-Aguilera, Oscar M. and Esteban, Gerard and Chioua, Mourad and Nikolić, Katarina and Agbaba, Danica and Moraleda, Ignacio and Iriepa, Isabel and Soriano, Elena and Samadi, Abdelouahid and Unzeta, Mercedes and Marco-Contelles, Jose",
year = "2014",
abstract = "The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] = 1.1 +/- 0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 = 600 +/- 80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] = 5,700 +/- 2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] = 3,950 +/- 94 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective hAChE and selective irreversible hMAO B inhibitor which might be considered as a promising compound for further development for the treatment of AD.",
publisher = "Dove Medical Press Ltd, Albany",
journal = "Drug Design Development and Therapy",
title = "Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids",
volume = "8",
pages = "1893-1910",
doi = "10.2147/DDDT.S69258"
}

Bautista-Aguilera, O. M., Esteban, G., Chioua, M., Nikolić, K., Agbaba, D., Moraleda, I., Iriepa, I., Soriano, E., Samadi, A., Unzeta, M.,& Marco-Contelles, J.. (2014). Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids. in Drug Design Development and Therapy
Dove Medical Press Ltd, Albany., 8, 1893-1910.
https://doi.org/10.2147/DDDT.S69258

Bautista-Aguilera OM, Esteban G, Chioua M, Nikolić K, Agbaba D, Moraleda I, Iriepa I, Soriano E, Samadi A, Unzeta M, Marco-Contelles J. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids. in Drug Design Development and Therapy. 2014;8:1893-1910.
doi:10.2147/DDDT.S69258 .

Bautista-Aguilera, Oscar M., Esteban, Gerard, Chioua, Mourad, Nikolić, Katarina, Agbaba, Danica, Moraleda, Ignacio, Iriepa, Isabel, Soriano, Elena, Samadi, Abdelouahid, Unzeta, Mercedes, Marco-Contelles, Jose, "Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids" in Drug Design Development and Therapy, 8 (2014):1893-1910,
https://doi.org/10.2147/DDDT.S69258 . .

TY  - JOUR
AU  - Bautista-Aguilera, Oscar M.
AU  - Esteban, Gerard
AU  - Bolea, Irene
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
AU  - Moraleda, Ignacio
AU  - Iriepa, Isabel
AU  - Samadi, Abdelouahid
AU  - Soriano, Elena
AU  - Unzeta, Mercedes
AU  - Marco-Contelles, Jose
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2158
AB  - The design, synthesis, and pharmacological evaluation of donepezil indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 +/- 1.4 nM) and moderately potent hMAO B (IC50 = 150 +/- 31 nM), EeAChE (IC50 = 190 +/- 10 nM), and eqBuChE (IC50 = 830 +/- 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD.
PB  - Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
T2  - European Journal of Medicinal Chemistry
T1  - Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease
VL  - 75
SP  - 82
EP  - 95
DO  - 10.1016/j.ejmech.2013.12.028
ER  - 

@article{
author = "Bautista-Aguilera, Oscar M. and Esteban, Gerard and Bolea, Irene and Nikolić, Katarina and Agbaba, Danica and Moraleda, Ignacio and Iriepa, Isabel and Samadi, Abdelouahid and Soriano, Elena and Unzeta, Mercedes and Marco-Contelles, Jose",
year = "2014",
abstract = "The design, synthesis, and pharmacological evaluation of donepezil indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 +/- 1.4 nM) and moderately potent hMAO B (IC50 = 150 +/- 31 nM), EeAChE (IC50 = 190 +/- 10 nM), and eqBuChE (IC50 = 830 +/- 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD.",
publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux",
journal = "European Journal of Medicinal Chemistry",
title = "Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease",
volume = "75",
pages = "82-95",
doi = "10.1016/j.ejmech.2013.12.028"
}

Bautista-Aguilera, O. M., Esteban, G., Bolea, I., Nikolić, K., Agbaba, D., Moraleda, I., Iriepa, I., Samadi, A., Soriano, E., Unzeta, M.,& Marco-Contelles, J.. (2014). Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease. in European Journal of Medicinal Chemistry
Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux., 75, 82-95.
https://doi.org/10.1016/j.ejmech.2013.12.028

Bautista-Aguilera OM, Esteban G, Bolea I, Nikolić K, Agbaba D, Moraleda I, Iriepa I, Samadi A, Soriano E, Unzeta M, Marco-Contelles J. Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease. in European Journal of Medicinal Chemistry. 2014;75:82-95.
doi:10.1016/j.ejmech.2013.12.028 .

Bautista-Aguilera, Oscar M., Esteban, Gerard, Bolea, Irene, Nikolić, Katarina, Agbaba, Danica, Moraleda, Ignacio, Iriepa, Isabel, Samadi, Abdelouahid, Soriano, Elena, Unzeta, Mercedes, Marco-Contelles, Jose, "Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease" in European Journal of Medicinal Chemistry, 75 (2014):82-95,
https://doi.org/10.1016/j.ejmech.2013.12.028 . .